Journal articles on the topic 'Glycinergic synaptic current'
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1
Donato, Roberta, and Andrea Nistri. "Differential Short-Term Changes in GABAergic or Glycinergic Synaptic Efficacy on Rat Hypoglossal Motoneurons." Journal of Neurophysiology 86, no. 2 (August 1, 2001): 565–74. http://dx.doi.org/10.1152/jn.2001.86.2.565.
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Using whole cell patch-clamp recording from hypoglossal motoneurons of a neonatal rat brain slice preparation, we investigated short-term changes in synaptic transmission mediated by GABA or glycine. In 1.5 mM extracellular Ca2+[Ca2+]o, pharmacologically isolated GABAergic or glycinergic currents were elicited by electrical stimulation of the reticular formation. At low stimulation frequency, glycinergic currents were larger and faster than GABAergic ones. GABAergic currents were strongly facilitated by pulse trains at 5 or 10 Hz without apparent depression. This phenomenon persisted after pharmacological block of GABABreceptors. Glycinergic currents were comparatively much less enhanced than GABAergic currents. One possible mechanism to account for this difference is that GABAergic currents decayed so slowly that consecutive responses summated over an incrementing baseline. However, while synaptic summation appeared at ≥10-Hz stimulation, at 5 Hz strong facilitation developed with minimal summation of GABA-mediated currents. Glycinergic currents decayed so fast that summation was minimal. As [Ca2+]o is known to shape short-term synaptic changes, we examined if varying [Ca2+]o could differentially affect facilitation of GABA- or glycine-operated synapses. With 5 mM [Ca2+]o, the frequency of spontaneous GABAergic or glycinergic currents appeared much higher but GABAergic current facilitation was blocked (and replaced by depression), whereas glycinergic currents remained slightly facilitated. [Ca2+]omanipulation thus brought about distinct processes responsible for facilitation of GABAergic or glycinergic transmission. Our data therefore demonstrate an unexpectedly robust, short-term increase in the efficiency of GABAergic synapses that can become at least as effective as glycinergic synapses.
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Ghavanini, Amer A., David A. Mathers, Hee-Soo Kim, and Ernest Puil. "Distinctive Glycinergic Currents With Fast and Slow Kinetics in Thalamus." Journal of Neurophysiology 95, no. 6 (June 2006): 3438–48. http://dx.doi.org/10.1152/jn.01218.2005.
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We examined functional properties of inhibitory postsynaptic currents (IPSCs) evoked by medial lemniscal stimulation, spontaneous IPSCs (sIPSCs), and single-channel, extrasynaptic currents evoked by glycine receptor agonists or γ-aminobutyric acid (GABA) in rat ventrobasal thalamus. We identified synaptic currents by reversal at ECl and sensitivity to elimination by strychnine, GABAA antagonists, or combined application. Glycinergic IPSCs featured short (about 12 ms) and long (about 80 ms) decay time constants. These fast and slow IPSCs occurred separately with monoexponential decays, or together with biexponential decay kinetics. Glycinergic sIPSCs decayed monoexponentially with time constants, matching fast and slow IPSCs. These findings were consistent with synaptic responses generated by two populations of glycine receptors, localized under different nerve terminals. Glycine, taurine, or β-alanine applied to excised membrane patches evoked short- and long-duration current bursts. Extrasynaptic burst durations resembled fast and slow IPSC time constants. The single, intermediate time constant (about 22 ms) of GABAAergic IPSCs cotransmitted with glycinergic IPSCs approximated the burst duration of extrasynaptic GABAA channels. We noted differences between synaptic and extrasynaptic receptors. Endogenously activated glycine and GABAA receptor channels had higher Cl− permeability than that of their extrasynaptic counterparts. The β-amino acids activated long-duration bursts at extrasynaptic glycine receptors, consistent with a role in detection of ambient taurine or β-alanine. Heterogenous kinetics and permeabilities implicate molecular and functional diversity in thalamic glycine receptors. Fast, intermediate, and slow inhibitory postsynaptic potential decays, mostly attributed to cotransmission by glycinergic and GABAergic pathways, allow for discriminative modulation and integration with voltage-dependent currents in ventrobasal neurons.
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McMenamin, Caitlin A., Laura Anselmi, R. Alberto Travagli, and Kirsteen N. Browning. "Developmental regulation of inhibitory synaptic currents in the dorsal motor nucleus of the vagus in the rat." Journal of Neurophysiology 116, no. 4 (October 1, 2016): 1705–14. http://dx.doi.org/10.1152/jn.00249.2016.
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Prior immunohistochemical studies have demonstrated that at early postnatal time points, central vagal neurons receive both glycinergic and GABAergic inhibitory inputs. Functional studies have demonstrated, however, that adult vagal efferent motoneurons receive only inhibitory GABAergic synaptic inputs, suggesting loss of glycinergic inhibitory neurotransmission during postnatal development. The purpose of the present study was to test the hypothesis that the loss of glycinergic inhibitory synapses occurs in the immediate postnatal period. Whole cell patch-clamp recordings were made from dorsal motor nucleus of the vagus (DMV) neurons from postnatal days 1–30, and the effects of the GABAA receptor antagonist bicuculline (1–10 μM) and the glycine receptor antagonist strychnine (1 μM) on miniature inhibitory postsynaptic current (mIPSC) properties were examined. While the baseline frequency of mIPSCs was not altered by maturation, perfusion with bicuculline either abolished mIPSCs altogether or decreased mIPSC frequency and decay constant in the majority of neurons at all time points. In contrast, while strychnine had no effect on mIPSC frequency, its actions to increase current decay time declined during postnatal maturation. These data suggest that in early postnatal development, DMV neurons receive both GABAergic and glycinergic synaptic inputs. Glycinergic neurotransmission appears to decline by the second postnatal week, and adult neurons receive principally GABAergic inhibitory inputs. Disruption of this developmental switch from GABA-glycine to purely GABAergic transmission in response to early life events may, therefore, lead to adverse consequences in vagal efferent control of visceral functions.
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TRAN, MY N., MATTHEW H. HIGGS, and PETER D. LUKASIEWICZ. "AMPA receptor kinetics limit retinal amacrine cell excitatory synaptic responses." Visual Neuroscience 16, no. 5 (September 1999): 835–42. http://dx.doi.org/10.1017/s0952523899165039.
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Amacrine cells that respond transiently to maintained illumination are thought to mediate transient inhibitory input to ganglion cells. The excitation of these transient amacrine cells is thought to be limited by inhibitory feedback to bipolar cells. We investigated the possibility that desensitizing AMPA and/or kainate (KA) receptors on amacrine cells might also limit the duration of amacrine cell excitation. To determine how these receptors might affect amacrine cell input and output, we made whole-cell recordings from amacrine and ganglion cells in the salamander retinal slice. The specific AMPA receptor antagonist GYKI-53655 blocked non-NMDA receptor-mediated amacrine cell excitatory postsynaptic currents (EPSCs) and kainate puff-elicited currents, indicating that AMPA, and not KA, receptors mediated the responses. Cyclothiazide, an agent that reduces AMPA receptor desensitization, increased the amplitude and duration of amacrine cell EPSCs. To measure the output of transient amacrine cells, we recorded glycinergic inhibitory postsynaptic currents (IPSCs) from ganglion cells, and found that these were also enhanced by cyclothiazide. Thus, prolongation of amacrine cell AMPA receptor activation enhanced amacrine cell output. Current responses elicited by puffing glycine onto ganglion cell dendrites were not affected by cyclothiazide, indicating that the enhancement of glycinergic IPSCs was not due to a direct effect on glycine receptors. These data suggest that rapid AMPA receptor desensitization and/or deactivation limits glycinergic amacrine cell excitation and the resulting inhibitory synaptic output.
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Tadros, M. A., K. E. Farrell, P. R. Schofield, A. M. Brichta, B. A. Graham, A. J. Fuglevand, and R. J. Callister. "Intrinsic and synaptic homeostatic plasticity in motoneurons from mice with glycine receptor mutations." Journal of Neurophysiology 111, no. 7 (April 1, 2014): 1487–98. http://dx.doi.org/10.1152/jn.00728.2013.
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Inhibitory synaptic inputs to hypoglossal motoneurons (HMs) are important for modulating excitability in brainstem circuits. Here we ask whether reduced inhibition, as occurs in three murine mutants with distinct naturally occurring mutations in the glycine receptor (GlyR), leads to intrinsic and/or synaptic homeostatic plasticity. Whole cell recordings were obtained from HMs in transverse brainstem slices from wild-type ( wt), spasmodic ( spd), spastic ( spa), and oscillator ( ot) mice (C57Bl/6, approximately postnatal day 21). Passive and action potential (AP) properties in spd and ot HMs were similar to wt. In contrast, spa HMs had lower input resistances, more depolarized resting membrane potentials, higher rheobase currents, smaller AP amplitudes, and slower afterhyperpolarization current decay times. The excitability of HMs, assessed by “gain” in injected current/firing-frequency plots, was similar in all strains whereas the incidence of rebound spiking was increased in spd. The difference between recruitment and derecruitment current (i.e., Δ I) for AP discharge during ramp current injection was more negative in spa and ot. GABAA miniature inhibitory postsynaptic current (mIPSC) amplitude was increased in spa and ot but not spd, suggesting diminished glycinergic drive leads to compensatory adjustments in the other major fast inhibitory synaptic transmitter system in these mutants. Overall, our data suggest long-term reduction in glycinergic drive to HMs results in changes in intrinsic and synaptic properties that are consistent with homeostatic plasticity in spa and ot but not in spd. We propose such plasticity is an attempt to stabilize HM output, which succeeds in spa but fails in ot.
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Buss, Robert R., and Pierre Drapeau. "Synaptic Drive to Motoneurons During Fictive Swimming in the Developing Zebrafish." Journal of Neurophysiology 86, no. 1 (July 1, 2001): 197–210. http://dx.doi.org/10.1152/jn.2001.86.1.197.
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The development of swimming behavior and the correlated activity patterns recorded in motoneurons during fictive swimming in paralyzed zebrafish larvae were examined and compared. Larvae were studied from when they hatch (after 2 days) and are first capable of locomotion to when they are active swimmers capable of capturing prey (after 4 days). High-speed (500 Hz) video imaging was used to make a basic behavioral characterization of swimming. At hatching and up to day 3, the larvae swam infrequently and in an undirected fashion. They displayed sustained bursts of contractions (‘burst swimming’) at an average frequency of 60–70 Hz that lasted from several seconds to a minute in duration. By day 4 the swimming had matured to a more frequent and less erratic “beat-and-glide” mode, with slower (∼35 Hz) beats of contractions for ∼200 ms alternating with glides that were twice as long, lasting from just a few cycles to several minutes overall. In whole cell current-clamp recordings, motoneurons displayed similar excitatory synaptic activity and firing patterns, corresponding to either fictive burst swimming (day 2–3) or beat-and-glide swimming (day 4). The resting potentials were similar at all stages (about −70 mV) and the motoneurons were depolarized (to about −40 mV) with generally non-overshooting action potentials during fictive swimming. The frequency of sustained inputs during fictive burst swimming and of repetitive inputs during fictive beat-and glide swimming corresponded to the behavioral contraction patterns. Fictive swimming activity patterns were eliminated by application of glutamate antagonists (kynurenic acid or 6-cyano-7-nitroquinoxalene-2,3-dione anddl-2-amino-5-phosphonovaleric acid) and were modified but maintained in the presence of the glycinergic antagonist strychnine. The corresponding synaptic currents underlying the synaptic drive to motoneurons during fictive swimming could be isolated under voltage clamp and consisted of cationic [glutamatergic postsynaptic currents (PSCs)] and anionic inputs (glycinergic PSCs). Either sustained or interrupted patterns of PSCs were observed during fictive burst or beat-and-glide swimming, respectively. During beat-and-glide swimming, a tonic inward current and rhythmic glutamatergic PSCs (∼35 Hz) were observed. In contrast, bursts of glycinergic PSCs occurred at a higher frequency, resulting in a more tonic pattern with little evidence for synchronized activity. We conclude that a rhythmic glutamatergic synaptic drive underlies swimming and that a tonic, shunting glycinergic input acts to more closely match the membrane time constant to the fast synaptic drive.
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CROOK, JOANNA D., ORIN S. PACKER, and DENNIS M. DACEY. "A synaptic signature for ON- and OFF-center parasol ganglion cells of the primate retina." Visual Neuroscience 31, no. 1 (November 27, 2013): 57–84. http://dx.doi.org/10.1017/s0952523813000461.
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AbstractIn the primate retina, parasol ganglion cells contribute to the primary visual pathway via the magnocellular division of the lateral geniculate nucleus, display ON and OFF concentric receptive field structure, nonlinear spatial summation, and high achromatic temporal–contrast sensitivity. Parasol cells may be homologous to the alpha-Y cells of nonprimate mammals where evidence suggests that N-methyl-D-aspartate (NMDA) receptor-mediated synaptic excitation as well as glycinergic disinhibition play critical roles in contrast sensitivity, acting asymmetrically in OFF- but not ON-pathways. Here, light-evoked synaptic currents were recorded in the macaque monkey retina in vitro to examine the circuitry underlying parasol cell receptive field properties. Synaptic excitation in both ON and OFF types was mediated by NMDA as well as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptors. The NMDA-mediated current–voltage relationship suggested high Mg2+ affinity such that at physiological potentials, NMDA receptors contributed ∼20% of the total excitatory conductance evoked by moderate stimulus contrasts and temporal frequencies. Postsynaptic inhibition in both ON and OFF cells was dominated by a large glycinergic “crossover” conductance, with a relatively small contribution from GABAergic feedforward inhibition. However, crossover inhibition was largely rectified, greatly diminished at low stimulus contrasts, and did not contribute, via disinhibition, to contrast sensitivity. In addition, attenuation of GABAergic and glycinergic synaptic inhibition left center–surround and Y-type receptive field structure and high temporal sensitivity fundamentally intact and clearly derived from modulation of excitatory bipolar cell output. Thus, the characteristic spatial and temporal–contrast sensitivity of the primate parasol cell arises presynaptically and is governed primarily by modulation of the large AMPA/kainate receptor-mediated excitatory conductance. Moreover, the negative feedback responsible for the receptive field surround must derive from a nonGABAergic mechanism.
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Oku, Y., S. Hülsmann, W. Zhang, and D. W. Richter. "Modulation of glycinergic synaptic current kinetics by octanol in mouse hypoglossal motoneurons." Pfl�gers Archiv European Journal of Physiology 438, no. 5 (September 17, 1999): 656–64. http://dx.doi.org/10.1007/s004240051090.
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Oku, Y., S. Hülsmann, W. Zhang, and D. W. Richter. "Modulation of glycinergic synaptic current kinetics by octanol in mouse hypoglossal motoneurons." Pflügers Archiv - European Journal of Physiology 438, no. 5 (October 1999): 656–64. http://dx.doi.org/10.1007/s004249900089.
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Xie (解瑞立), Ruili, and Paul B. Manis. "Glycinergic synaptic transmission in the cochlear nucleus of mice with normal hearing and age-related hearing loss." Journal of Neurophysiology 110, no. 8 (October 15, 2013): 1848–59. http://dx.doi.org/10.1152/jn.00151.2013.
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The principal inhibitory neurotransmitter in the mammalian cochlear nucleus (CN) is glycine. During age-related hearing loss (AHL), glycinergic inhibition becomes weaker in CN. However, it is unclear what aspects of glycinergic transmission are responsible for weaker inhibition with AHL. We examined glycinergic transmission onto bushy cells of the anteroventral CN in normal-hearing CBA/CaJ mice and in DBA/2J mice, a strain that exhibits an early onset AHL. Glycinergic synaptic transmission was examined in brain slices of mice at 10–15 postnatal days old, 20–35 days old, and at 6–7 mo old. Spontaneous inhibitory postsynaptic current (sIPSC) event frequency and amplitude were the same among all three ages in both strains of mice. However, the amplitudes of IPSCs evoked (eIPSC) from stimulating the dorsal CN were smaller, and the failure rate was higher, with increasing age due to decreased quantal content in both mouse strains, independent of hearing status. The coefficient of variation of the eIPSC amplitude also increased with age. The decay time constant (τ) of sIPSCs and eIPSCs were constant in CBA/CaJ mice at all ages, but were significantly slower in DBA/2J mice at postnatal days 20–35, following the onset of AHL, and not at earlier or later ages. Our results suggest that glycinergic inhibition at the synapses onto bushy cells becomes weaker and less reliable with age through changes in release. However, the hearing loss in DBA/2J mice is accompanied by a transiently enhanced inhibition, which could disrupt the balance of excitation and inhibition.
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Lim, Rebecca, Robert J. Callister, and Alan M. Brichta. "An Increase in Glycinergic Quantal Amplitude and Frequency During Early Vestibular Compensation in Mouse." Journal of Neurophysiology 103, no. 1 (January 2010): 16–24. http://dx.doi.org/10.1152/jn.91223.2008.
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The process of vestibular compensation includes both behavioral and neuronal recovery after unilateral loss of peripheral vestibular organs. The mechanisms that underlie this process are poorly understood. Previous research has shown the presence of both γ-aminobutyric acid type A (GABAA) and glycine receptors in the medial vestibular nuclei (MVN). It has been suggested that inhibitory transmission mediated by these receptors may have a role in recovery during vestibular compensation. This study investigated changes in fast inhibitory synaptic transmission of GABAAergic and glycinergic quantal events after unilateral labyrinthectomy (UL) at three different time points. Mice were anesthetized and peripheral vestibular organs were removed from one side of the head. After recovery, transverse brain stem sections (300 μm) were prepared from mice that had undergone UL either 4 hours, 2 days, or 7 days earlier. Our experiments do not show evidence for alterations in synaptic GABAA receptor properties in MVN neurons after UL at any time point investigated. In contrast, during early vestibular compensation (4 hours post UL) there is a significant increase in the glycinergic quantal current amplitude in contralesional MVN neurons compared with control. Our results also show an increase in the frequency of glycinergic quantal events of both ipsi- and contralesional MVN neurons during this early period. We suggest that changes in both pre- and postsynaptic glycine receptor mediated inhibitory synaptic transmission after sensory loss is an important mechanism by which neuronal discharge patterns can be modulated.
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Shao, Mei, June C. Hirsch, and Kenna D. Peusner. "Emergence of Action Potential Generation and Synaptic Transmission in Vestibular Nucleus Neurons." Journal of Neurophysiology 96, no. 3 (September 2006): 1215–26. http://dx.doi.org/10.1152/jn.00180.2006.
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Principal cells of the chick tangential nucleus are vestibular nucleus neurons in the hindbrain. Although detailed information is available on the morphogenesis of principal cells and synaptogenesis of primary vestibular fibers, this is the first study of their early functional development, when vestibular terminals emerge at embryonic days 10 and 13 (E10 and E13). At E10, 60% of principal cells generated spikes on depolarization, whereas 50% exhibited excitatory postsynaptic currents (EPSCs) on vestibular-nerve stimulation. The frequency was 0.2 Hz for glutamatergic spontaneous EPSCs (sEPSCs) at −60 mV, and 0.6 Hz for spontaneous inhibitory postsynaptic current (sIPSC) at +10 mV and completely GABAergic. All of these synaptic events were TTX-insensitive, miniature events. At E13, 50% of principal cells generated spikes on depolarization and 82% exhibited EPSCs on vestibular-nerve stimulation. The frequency was 0.7 Hz for sEPSCs at −60 mV, and 0.8 Hz for sIPSCs at +10 mV. Most principal cells had sIPSCs composed of both GABAergic (75%) and glycinergic (25%) events, but a few cells had only GABAergic sIPSCs. TTX decreased the frequency of EPSCs by 12%, and the IPSCs by 17%. In summary, at E10, some principal cells generated immature spikes on depolarization and EPSCs on vestibular-nerve stimulation. At E10, GABAergic events predominated, AMPA events had low frequencies, and glycinergic activity was absent. By E13, glycinergic events first appeared. This data were compared systematically to that obtained from the late-term embryo and hatchling to reveal the long-term sequence of changes in synaptic events and excitability and offer a broader understanding of how the vestibular system is assembled during development.
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Fischl, Matthew J., Sonia R. Weimann, Michael G. Kearse, and R. Michael Burger. "Slowly emerging glycinergic transmission enhances inhibition in the sound localization pathway of the avian auditory system." Journal of Neurophysiology 111, no. 3 (February 1, 2014): 565–72. http://dx.doi.org/10.1152/jn.00640.2013.
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Localization of low-frequency acoustic stimuli is processed in dedicated neural pathways where coincidence-detecting neurons compare the arrival time of sound stimuli at the two ears, or interaural time disparity (ITD). ITDs occur in the submillisecond range, and vertebrates have evolved specialized excitatory and inhibitory circuitry to compute these differences. Glycinergic inhibition is a computationally significant and prominent component of the mammalian ITD pathway. However, evidence for glycinergic transmission is limited in birds, where GABAergic inhibition has been thought to be the dominant or exclusive inhibitory transmitter. Indeed, previous work showed that GABA antagonists completely eliminate inhibition in avian nuclei specialized for processing temporal features of sound, nucleus magnocellularis (NM) and nucleus laminaris (NL). However, more recent work shows that glycine is coexpressed with GABA in synaptic terminals apposed to neurons in both nuclei (Coleman WL, Fischl MJ, Weimann SR, Burger RM. J Neurophysiol 105: 2405–2420, 2011; Kuo SP, Bradley LA, Trussell LO. J Neurosci 29: 9625–9634, 2009). Here we show complementary evidence of functional glycine receptor (GlyR) expression in NM and NL. Additionally, we show that glycinergic input can be evoked under particular stimulus conditions. Stimulation at high but physiologically relevant rates evokes a slowly emerging glycinergic response in NM and NL that builds over the course of the stimulus. Glycinergic response magnitude was stimulus rate dependent, representing 18% and 7% of the total inhibitory current in NM and NL, respectively, at the end of the 50-pulse, 200-Hz stimulus. Finally, we show that the glycinergic component is functionally relevant, as its elimination reduced inhibition of discharges evoked by current injection into NM neurons.
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Thakre, Prajwal P., and Mark C. Bellingham. "Capsaicin causes robust reduction in glycinergic transmission to rat hypoglossal motor neurons via a TRPV1-independent mechanism." Journal of Neurophysiology 121, no. 4 (April 1, 2019): 1535–42. http://dx.doi.org/10.1152/jn.00059.2019.
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The effect of capsaicin on glycinergic synaptic transmission to juvenile rat hypoglossal motor neurons in acute brainstem slices was evaluated in the presence of TTX. Capsaicin caused a robust decrease in miniature IPSC frequency, amplitude, and half-width, showing that this effect is independent of action potential generation. In the presence of capsazepine, a classic TRPV1 antagonist, capsaicin was still able to reduce spontaneous inhibitory postsynaptic current (IPSC) amplitude and frequency. We further investigated whether the effect of capsaicin on glycinergic transmission to hypoglossal motor neurons is pre- or postsynaptic in nature by recording pairs of evoked IPSCs. Interestingly, capsaicin also reduced evoked IPSC amplitude without affecting paired-pulse ratio, indicating a postsynaptic mechanism of action. Significant reduction was also observed in evoked IPSC half-width, rise time, and decay tau. We also show that capsaicin does not have any effect on either transient (It) or sustained (Is) potassium currents. Finally, we also show that the hyperpolarization-activated cationic current (Ih) also remains unchanged after capsaicin application. NEW & NOTEWORTHY Capsaicin reduces the amplitude of quantal and evoked glycinergic inhibitory neurotransmission to brainstem motor neurons without altering activity-dependent transmitter release. This effect of capsaicin is not due to activation of TRPV1 receptors, as it is not blocked by capsazepine, a TRPV1 receptor antagonist. Capsaicin does not alter voltage-dependent potassium current or the hyperpolarization-activated cationic current in brainstem motor neurons.
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Mariqueo, Trinidad A., Adolfo Agurto, Braulio Muñoz, Loreto San Martin, Cesar Coronado, Eduardo J. Fernández-Pérez, Pablo Murath, Andrea Sánchez, Gregg E. Homanics, and Luis G. Aguayo. "Effects of ethanol on glycinergic synaptic currents in mouse spinal cord neurons." Journal of Neurophysiology 111, no. 10 (May 15, 2014): 1940–48. http://dx.doi.org/10.1152/jn.00789.2013.
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Ethanol increased the frequency of miniature glycinergic currents [miniature inhibitory postsynaptic currents (mIPSCs)] in cultured spinal neurons. This effect was dependent on intracellular calcium augmentation, since preincubation with BAPTA (an intracellular calcium chelator) or thapsigargin [a sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor] significantly attenuated this effect. Similarly, U73122 (a phospholipase C inhibitor) or 2-aminoethoxydiphenyl borate [2-APB, an inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) inhibitor] reduced this effect. Block of ethanol action was also achieved after preincubation with Rp-cAMPS, inhibitor of the adenylate cyclase (AC)/PKA signaling pathway. These data suggest that there is a convergence at the level of IP3R that accounts for presynaptic ethanol effects. At the postsynaptic level, ethanol increased the decay time constant of mIPSCs in a group of neurons (30 ± 10% above control, n = 13/26 cells). On the other hand, the currents activated by exogenously applied glycine were consistently potentiated (55 ± 10% above control, n = 11/12 cells), which suggests that ethanol modulates synaptic and nonsynaptic glycine receptors (GlyRs) in a different fashion. Supporting the role of G protein modulation on ethanol responses, we found that a nonhydrolyzable GTP analog [guanosine 5′- O-(3-thiotriphosphate) (GTPγS)] increased the decay time constant in ∼50% of the neurons (28 ± 12%, n = 11/19 cells) but potentiated the glycine-activated Cl− current in most of the neurons examined (83 ± 29%, n = 7/9 cells). In addition, confocal microscopy showed that α1-containing GlyRs colocalized with Gβ and Piccolo (a presynaptic cytomatrix protein) in ∼40% of synaptic receptor clusters, suggesting that colocalization of Gβγ and GlyRs might account for the difference in ethanol sensitivity at the postsynaptic level.
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Wang, Xin, Zheng-Gui Huang, Olga Dergacheva, Evguenia Bouairi, Christopher Gorini, Christopher Stephens, Michael C. Andresen, and David Mendelowitz. "Ketamine Inhibits Inspiratory-evoked γ-Aminobutyric Acid and Glycine Neurotransmission to Cardiac Vagal Neurons in the Nucleus Ambiguus." Anesthesiology 103, no. 2 (August 1, 2005): 353–59. http://dx.doi.org/10.1097/00000542-200508000-00019.
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Background Ketamine can be used for perioperative pain management as well as a dissociative anesthetic agent in emergency situations. However, ketamine can induce both cardiovascular and respiratory depression, especially in pediatric patients. Although ketamine has usually been regarded as sympathoexcitatory, recent work has demonstrated that ketamine has important actions on parasympathetic cardiac vagal efferent activity. The current study tests the hypothesis that ketamine, at clinical relevant concentrations, alters central cardiorespiratory interactions in the brainstem and, in particular, the inspiration-evoked increase in gamma-aminobutyric acid-mediated and glycinergic neurotransmission to parasympathetic cardiac efferent neurons. Methods Cardiac vagal neurons were identified by the presence of a retrograde fluorescent tracer. Respiratory evoked gamma-aminobutyric acid-mediated and glycinergic synaptic currents were recorded in cardiac vagal neurons using whole cell patch clamp techniques while spontaneous rhythmic respiratory activity was recorded simultaneously. Results : Ketamine, at concentrations from 0.1 to 10 microM, evoked a concentration-dependent inhibition of inspiratory burst frequency. Inspiration-evoked gamma-aminobutyric acid-mediated neurotransmission to cardiac vagal neurons was inhibited at ketamine concentrations of 0.5 and 1 microM. The increase in glycinergic activity to cardiac vagal neurons during inspiration was also inhibited at ketamine concentrations of 0.5 and 1 microM. Conclusions At clinically relevant concentrations (0.5 and 1 microM), ketamine alters central respiratory activity and diminishes both inspiration-evoked gamma-aminobutyric acid-mediated and glycinergic neurotransmission to parasympathetic cardiac efferent neurons. This reduction in inhibitory neurotransmission to cardiac vagal neurons is likely responsible for the compromised respiratory sinus arrhythmia that occurs with ketamine anesthesia.
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O'BRIEN, BRENDAN J., RANDAL C. RICHARDSON, and DAVID M. BERSON. "Inhibitory network properties shaping the light evoked responses of cat alpha retinal ganglion cells." Visual Neuroscience 20, no. 4 (July 2003): 351–61. http://dx.doi.org/10.1017/s0952523803204016.
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Cat retinal ganglion cells of the Y (or alpha) type respond to luminance changes opposite those preferred by their receptive-field centers with a transient hyperpolarization. Here, we examine the spatial organization and synaptic basis of this light response by means of whole-cell current-clamp recordings made in vitro. The hyperpolarization was largest when stimulus spots approximated the size of the receptive-field center, and diminished substantially for larger spots. The hyperpolarization was largely abolished by bath application of strychnine, a blocker of glycinergic inhibition. Picrotoxin, an antagonist of ionotropic GABA receptors, greatly reduced the attenuation of the hyperpolarizing response for large spots. The data are consistent with a model in which (1) the hyperpolarization reflects inhibition by glycinergic amacrine cells of bipolar terminals presynaptic to the alpha cells, and perhaps direct inhibition of the alpha cell as well; and (2) the attenuation of the hyperpolarization by large spots reflects surround inhibition of the glycinergic amacrine by GABAergic amacrine cells. This circuitry may moderate nonlinearities in the alpha-cell light response and could account for some excitatory and inhibitory influences on alpha cells known to arise from outside the classical receptive field.
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Zhang, Jian, Chang-Sub Jung, and Malcolm M. Slaughter. "Serial inhibitory synapses in retina." Visual Neuroscience 14, no. 3 (May 1997): 553–63. http://dx.doi.org/10.1017/s0952523800012219.
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AbstractWhole-cell voltage clamp in the retinal slice and intracellular current clamp in the intact retina were used to study inhibitory interactions in the inner plexiform layer. Picrotoxin or strychnine reduced inhibitory, light-evoked currents in a majority of ganglion cells. However, in nearly a third of the ganglion cells, each of these antagonists enhanced the inhibitory synaptic current. All inhibitory current was blocked by the addition of the other antagonist. This indicates a cross-inhibition between GABAergic and glycinergic feedforward pathways. Blocking of GABAARs with SR95531 shortened the time course of both excitatory and inhibitory synaptic currents in ganglion cells. Application of picrotoxin, which blocked both GABAARs and GABACRs, produced the opposite effect. Recordings in the intact retina indicated that the light responses of ON bipolar cells, sustained ON, and transient ON-OFF third-order neurons were all made more transient by SR95531 and made more sustained by picrotoxin. The data suggest that a GABAC feedback pathway to bipolar cells makes light responses more phasic and that this feedback is inhibited through a GABAAR pathway. Consequently, the balance between GABAAR and GABACR inhibition regulates the time course of inputs to ganglion cells.
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Liu, Tao, Tsugumi Fujita, and Eiichi Kumamoto. "Acetylcholine and norepinephrine mediate GABAergic but not glycinergic transmission enhancement by melittin in adult rat substantia gelatinosa neurons." Journal of Neurophysiology 106, no. 1 (July 2011): 233–46. http://dx.doi.org/10.1152/jn.00838.2010.
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GABAergic and glycinergic inhibitory synaptic transmissions in substantia gelatinosa (SG; lamina II of Rexed) neurons of the spinal dorsal horn play an important role in regulating nociceptive transmission from the periphery. It has not yet been well known whether each of the inhibitory transmissions plays a distinct role in the regulation. We report an involvement of neurotransmitters in GABAergic but not glycinergic transmission enhancement produced by the PLA2 activator melittin, where the whole-cell patch-clamp technique is applied to the SG neurons of adult rat spinal cord slices. Glycinergic but not GABAergic spontaneous inhibitory postsynaptic current (sIPSC) was increased in frequency and amplitude by melittin in the presence of nicotinic, muscarinic acetylcholine, and α1-adrenergic receptor antagonists (mecamylamine, atropine, and WB-4101, respectively). GABAergic transmission enhancement produced by melittin was unaffected by the 5-hydroxytryptamine 3 receptor and P2X receptor antagonists (ICS-205,930 and pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid, respectively). Nicotinic and muscarinic acetylcholine receptor agonists [(−)-nicotine and carbamoylcholine, respectively] and norepinephrine, as well as melittin, increased GABAergic sIPSC frequency and amplitude. A repeated application of (−)-nicotine, carbamoylcholine, and norepinephrine, but not melittin, at an interval of 30 min produced a similar transmission enhancement. These results indicate that melittin produces the release of acetylcholine and norepinephrine, which activate (nicotinic and muscarinic) acetylcholine and α1-adrenergic receptors, respectively, resulting in GABAergic but not glycinergic transmission enhancement in SG neurons. The desensitization of a system leading to the acetylcholine and norepinephrine release is slow in recovery. This distinction in modulation between GABAergic and glycinergic transmissions may play a role in regulating nociceptive transmission.
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Wollman, Lila Buls, Richard B. Levine, and Ralph F. Fregosi. "Developmental nicotine exposure alters glycinergic neurotransmission to hypoglossal motoneurons in neonatal rats." Journal of Neurophysiology 120, no. 3 (September 1, 2018): 1135–42. http://dx.doi.org/10.1152/jn.00600.2017.
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We tested the hypothesis that nicotine exposure in utero and after birth [developmental nicotine exposure (DNE)] disrupts development of glycinergic synaptic transmission to hypoglossal motoneurons (XIIMNs). Glycinergic spontaneous and miniature inhibitory postsynaptic currents (sIPSC/mIPSC) were recorded from XIIMNs in brain stem slices from 1- to 5-day-old rat pups of either sex, under baseline conditions and following stimulation of nicotinic acetylcholine (ACh) receptors with nicotine (i.e., an acute nicotine challenge). Under baseline conditions, there were no significant effects of DNE on the amplitude or frequency of either sIPSCs or mIPSCs. In addition, DNE did not alter the magnitude of the whole cell current evoked by bath application of glycine, consistent with an absence of change in postsynaptic glycine-mediated conductance. An acute nicotine challenge (bath application of 0.5 μM nicotine) increased sIPSC frequency in the DNE cells, but not control cells. In contrast, nicotine challenge did not change mIPSC frequency in either control or DNE cells. In addition, there were no significant changes in the amplitude of either sIPSCs or mIPSCs in response to nicotine challenge. The increased frequency of sIPSCs in response to an acute nicotine challenge in DNE cells reflects an enhancement of action potential-mediated input from glycinergic interneurons to hypoglossal motoneurons. This could lead to more intense inhibition of hypoglossal motoneurons in response to exogenous nicotine or endogenous ACh. The former would occur with smoking or e-cigarette use while the latter occurs with changes in sleep state and with hypercapnia. NEW & NOTEWORTHY Here we show that perinatal nicotine exposure does not impact baseline glycinergic neurotransmission to hypoglossal motoneurons but enhances glycinergic inputs to hypoglossal motoneurons in response to activation of nicotinic acetylcholine (ACh) receptors with acute nicotine. Given that ACh is the endogenous ligand for nicotinic ACh receptors, the latter reveals a potential mechanism whereby perinatal nicotine exposure alters motor function under conditions where ACh release increases, such as the transition from non-rapid-eye movement to rapid-eye movement sleep, and during hypercapnia.
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van Zundert, Brigitte, Francisco J. Alvarez, Gonzalo E. Yevenes, Juan G. Cárcamo, Juan Carlos Vera, and Luis G. Aguayo. "Glycine Receptors Involved in Synaptic Transmission Are Selectively Regulated by the Cytoskeleton in Mouse Spinal Neurons." Journal of Neurophysiology 87, no. 1 (January 1, 2002): 640–44. http://dx.doi.org/10.1152/jn.00455.2001.
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Using whole cell patch-clamp recordings, we examined the effect of colchicine, a microtubule disrupter, on the properties of glycine receptors (GlyRs) in cultured spinal cord neurons. Confocal microscopy revealed that colchicine treatment effectively altered microtubule bundles and neuronal morphology. Application of colchicine via the culture media or the patch-pipette, however, did not affect the whole cell current rundown (73 ± 6% of control after 1 h), the sensitivity of the GlyR to glycine (EC50 = 29 ± 1 μM), or strychnine inhibition (47 ± 5% of control after 100 nM strychnine). On the other hand, colchicine dialyzed for 25 min via the patch pipette selectively reduced the quantal amplitude of spontaneous glycinergic miniature inhibitory postsynaptic currents (mIPSCs) to 68 ± 5% of control. This effect was specific for GlyRs since synaptic events mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and GABAA receptors were unchanged. In conclusion, this study indicates that microtubules can regulate the function of GlyRs involved in inhibitory synaptic transmission.
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Ziskind-Conhaim, Lea, Linying Wu, and Eric P. Wiesner. "Persistent Sodium Current Contributes to Induced Voltage Oscillations in Locomotor-Related Hb9 Interneurons in the Mouse Spinal Cord." Journal of Neurophysiology 100, no. 4 (October 2008): 2254–64. http://dx.doi.org/10.1152/jn.90437.2008.
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Neurochemically induced membrane voltage oscillations and firing episodes in spinal excitatory interneurons expressing the HB9 protein (Hb9 INs) are synchronous with locomotor-like rhythmic motor outputs, suggesting that they contribute to the excitatory drive of motoneurons during locomotion. Similar to central pattern generator neurons in other systems, Hb9 INs are interconnected via electrical coupling, and their rhythmic activity does not depend on fast glutamatergic synaptic transmission. The primary objective of this study was to determine the contribution of fast excitatory and inhibitory synaptic transmission and subthreshold voltage-dependent currents to the induced membrane oscillations in Hb9 INs in the postnatal mouse spinal cord. The non- N-methyl-d-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced the amplitude of voltage oscillations but did not alter their frequency. CNQX suppressed rhythmic motor activity. Blocking glycine and GABAA receptor-mediated inhibitory synapses as well as cholinergic transmission did not change the properties of CNQX-resistant membrane oscillations. However, disinhibition triggered new episodes of slow motor bursting that were not correlated with induced locomotor-like rhythms in Hb9 INs. Our observations indicated that fast excitatory and inhibitory synaptic inputs did not control the frequency of induced rhythmic activity in Hb9 INs. We next examined the contribution of persistent sodium current ( INaP) to subthreshold membrane oscillations in the absence of primary glutamatergic, GABAergic and glycinergic synaptic drive to Hb9 INs. Low concentrations of riluzole that blocked the slow-inactivating component of sodium current gradually suppressed the amplitude and reduced the frequency of voltage oscillations. Our finding that INaP regulates locomotor-related rhythmic activity in Hb9 INs independently of primary synaptic transmission supports the concept that these neurons constitute an integral component of the rhythmogenic locomotor network in the mouse spinal cord.
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Moore, David R., Vibhakar C. Kotak, and Dan H. Sanes. "Commissural and Lemniscal Synaptic Input to the Gerbil Inferior Colliculus." Journal of Neurophysiology 80, no. 5 (November 1, 1998): 2229–36. http://dx.doi.org/10.1152/jn.1998.80.5.2229.
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Moore, David R., Vibhakar C. Kotak, and Dan H. Sanes. Commissural and lemniscal synaptic input to the gerbil inferior colliculus. J. Neurophysiol. 80: 2229–2236, 1998. The central nucleus of the inferior colliculus (ICC) receives direct inputs, bilaterally, from all auditory brain stem nuclear groups. To evaluate the contribution made to gerbil ICC neuron physiology by two major afferent pathways, we examined the synaptic responses evoked by direct stimulation of the commissure of the inferior colliculus (CIC) and the ipsilateral lateral lemniscus (LL). Frontal midbrain slices were obtained from postnatal day (P) 9–P19 gerbils, and whole cell recordings were made under current- ( n = 22) or voltage-clamp ( n = 52) conditions. Excitatory and inhibitory synaptic responses were characterized by sequentially exposing the slice to ionotropic glutamate receptor antagonists [6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) + aminophosphonpentanoic acid (AP-5), or kynurenic acid)], a γ-aminobutryic acid type A receptor antagonist (bicuculline), and a glycine receptor antagonist (strychnine). In current clamp, LL stimulation typically produced a short latency depolarization followed by a longer duration hyperpolarization. The depolarization was abolished by AP-5 + CNQX, and the remaining inhibitory potential displayed either bicuculline or strychnine sensitivity. In voltage clamp, 79% of ICC neurons displayed synaptic currents after stimulation of each pathway. The synaptic currents were typically complex waveforms, and ionotropic glutamate receptor antagonists reduced inward currents at a holding potential of −80 mV in the majority of neurons. In addition, this treatment reduced outward synaptic currents at a holding potential of −20 mV, indicating that inhibitory interneuronal input was often activated by LL or CIC afferents. A minority of neurons had synaptic currents that were unaffected by glutamate receptor antagonists, but it was more common for CIC-evoked currents to be unaffected (38%) rather than LL-evoked currents (22%). The CIC provided a strong inhibitory input that was almost exclusively GABAergic, whereas the LL inhibition often included a glycinergic component. These experiments have shown that the CIC provides a major glutamatergic and GABAergic input to most ICC neurons. However, much of the inhibitory input from both the CIC and the LL appears to be mediated by interneuronal connections.
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Faber, D. S., and H. Korn. "Unitary conductance changes at teleost Mauthner cell glycinergic synapses: a voltage-clamp and pharmacologic analysis." Journal of Neurophysiology 60, no. 6 (December 1, 1988): 1982–99. http://dx.doi.org/10.1152/jn.1988.60.6.1982.
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1. The magnitude and kinetics of inhibitory postsynaptic currents (IPSCs) evoked in the goldfish Mauthner (M-) cell by intracellular stimulation of identified presynaptic interneurons (unitary responses) and by activation of the recurrent collateral network were determined with single-and double electrode voltage-clamp techniques. 2. The peak magnitude of the inhibitory conductance changes were 5610 +/- 4800 nS (mean +/- SD; n = 13) for the collateral response, and 144 +/- 44 nS (n = 7) for the unitary IPSCs. These synaptic conductances, which are due to the opening of Cl- channels, were independent of the degree of Cl- -loading of the M-cell. 3. The peak amplitude of the collateral inhibitory postsynaptic potential (IPSP) was a constant fraction (0.52 +/- 0.06) of the driving force, which was determined from current-voltage plots for both types of IPSCs and ranged from 10 to 37 mV. These findings confirm indirect measurements from previous current-clamp studies and validate the normalization procedure used to previously calculate synaptic conductances from IPSP amplitudes, a method that therefore may be applicable to other central neurons. 4. At the resting membrane potential, the rise time of the unitary IPSCs was 0.34 +/- 0.07 ms (n = 18), whereas their decay was exponential, with a time constant of 5.7 +/- 1.1 ms (n = 16). 5. Iontophoretic and intramuscular applications of the glycine antagonist strychnine reduced or blocked M-cell inhibitory responses, without altering the excitability of the presynaptic neurons, or the driving force. 6. Amplitude fluctuations of unitary IPSPs recorded during partial blockade by strychnine were analyzed according to a binomial model of quantal transmitter release. In one experimental series, comparison of the binomial parameters before and after applying the antagonist indicated that only quantal size, q, was reduced, whereas n, the number of available release units, and p, the probability of release, were unaffected by strychnine. In a second series, the individual presynaptic cells were injected with horseradish peroxidase (HRP), and it was found that the correlation between n and the number of stained presynaptic boutons and, therefore, of active zones, was maintained in the presence of the drug. No evidence was found for silent synapses in these conditions. 7. The quantal conductance, gq, was estimated from the binomially derived quantal size, in millivolts, and the voltage-clamp measurements of the IPSP driving force and M-cell input conductance. gq averaged 21.5 nS in control conditions and 12.3 nS in the presence of strychnine.(ABSTRACT TRUNCATED AT 400 WORDS)
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Eulenburg, Volker, and Swen Hülsmann. "Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1." International Journal of Molecular Sciences 23, no. 5 (February 25, 2022): 2561. http://dx.doi.org/10.3390/ijms23052561.
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In addition to being involved in protein biosynthesis and metabolism, the amino acid glycine is the most important inhibitory neurotransmitter in caudal regions of the brain. These functions require a tight regulation of glycine concentration not only in the synaptic cleft, but also in various intracellular and extracellular compartments. This is achieved not only by confining the synthesis and degradation of glycine predominantly to the mitochondria, but also by the action of high-affinity large-capacity glycine transporters that mediate the transport of glycine across the membranes of presynaptic terminals or glial cells surrounding the synapses. Although most cells at glycine-dependent synapses express more than one transporter with high affinity for glycine, their synergistic functional interaction is only poorly understood. In this review, we summarize our current knowledge of the two high-affinity transporters for glycine, the sodium-dependent glycine transporters 1 (GlyT1; SLC6A9) and 2 (GlyT2; SLC6A5) and the alanine–serine–cysteine-1 transporter (Asc-1; SLC7A10).
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Shao, Xuesi M., and Jack L. Feldman. "Respiratory Rhythm Generation and Synaptic Inhibition of Expiratory Neurons in Pre-Bötzinger Complex: Differential Roles of Glycinergic and GABAergic Neural Transmission." Journal of Neurophysiology 77, no. 4 (April 1, 1997): 1853–60. http://dx.doi.org/10.1152/jn.1997.77.4.1853.
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Shao, Xuesi M. and Jack L. Feldman. Respiratory rhythm generation and synaptic inhibition of expiratory neurons in pre-Bötzinger complex: differential roles of glycinergic and GABAergic neural transmission. J. Neurophysiol. 77: 1853–1860, 1997. A key distinction between neural pacemaker and conventional network models for the generation of breathing rhythm in mammals is whether phasic reciprocal inhibitory interactions between inspiratory and expiratory neurons are required. In medullary slices from neonatal rats generating respiratory-related rhythm, we measured the phasic inhibitory inputs to expiratory neurons with the use of whole cell patch clamp in the hypothesized rhythm generation site, the pre-Bötzinger complex (pre-BötC). Expiratory neurons, which generate tonic impulse activity during the expiratory period, exhibited inhibitory postsynaptic potentials (IPSPs) synchronized to the periodic inspiratory bursts of the hypoglossal nerve root (XIIn). Bath application of the glycine receptor antagonist strychnine (STR; 5–10 μM) reversibly blocked these inspiratory-phase IPSPs, whereas the γ-aminobutyric acid-A (GABAA) receptor antagonist bicuculline (BIC; 10–100 μM) had no effect on these IPSPs. Replacing the control in vitro bathing solution with a Cl−-free solution also abolished these IPSPs. Respiratory-related rhythmic activity was not abolished when inspiratory-phase IPSPs were blocked. The frequency and strength of XIIn rhythmic activity increased and seizurelike activity was produced when either STR, BIC, or Cl−-free solution was applied. Inspiratory-phase IPSPs were stable after establishment of whole cell patch conditions (patch pipettes contained 7 mM Cl−). Under voltage clamp, the reversal potential of inspiratory-phase inhibitory postsynaptic currents (IPSCs) was −75 mV. The current-voltage ( I- V) curve for IPSCs shifted to the right when extracellular Cl− concentration was reduced by 50% (70 mM) and the reversal potential was reduced to −60 mV, close to the new Cl− Nernst potential. In tetrodotoxin (0.5 μM) under voltage clamp (holding potential = −45 mV), local application of glycine (1 mM) over pre-BötC induced an outward current and an increase in membrane conductance in expiratory neurons. The effect was blocked by bath application of STR (0.8–1 μM). Local application of the GABAA receptor agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 1 mM) induced an outward current and an increase in membrane conductance that was blocked by BIC (10–100 mM). Under voltage clamp (holding potential = −45 mV), we analyzed spontaneous IPSCs during expiration in expiratory neurons. Bath application of BIC (10 μM) reduced the IPSC frequency (from 2.2 to 0.3 per s), whereas the inspiratory-phase IPSCs did not change. Bath application of STR (8–10 μM) abolished both IPSCs. These results indicate that 1) reciprocal inhibition of expiratory neurons is glycinergic and mediated by a glycine-activated Cl− channel that is not required for respiratory-related rhythm generation in neonatal rat medullary slices; 2) endogenous GABA and glycine modulate the excitability of respiratory neurons and affect respiratory pattern in the slice preparation; 3) both glycine and GABAA receptors are found on pre-BötC expiratory neurons, and these receptors are sensitive to STR and BIC, respectively; 4) glycine and GABAA inhibitory mechanisms play different functional roles in expiratory neurons: both glycine and GABAA receptors modulate neuronal excitability, whereas glycinergic transmission alone is responsible for reciprocal inhibition; and 5) intracellular Cl− concentration in these neonatal expiratory neurons is similar to that in adults.
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Singer, Joshua H., and Albert J. Berger. "Contribution of Single-Channel Properties to the Time Course and Amplitude Variance of Quantal Glycine Currents Recorded in Rat Motoneurons." Journal of Neurophysiology 81, no. 4 (April 1, 1999): 1608–16. http://dx.doi.org/10.1152/jn.1999.81.4.1608.
Full textAbstract:
Contribution of single-channel properties to the time course and amplitude variance of quantal glycine currents recorded in rat motoneurons. The amplitude of spontaneous, glycinergic miniature inhibitory postsynaptic currents (mIPSCs) recorded in hypoglossal motoneurons (HMs) in an in vitro brain stem slice preparation increased over the first 3 postnatal weeks, from 42 ± 6 pA in neonate (P0–3) to 77 ± 11 pA in juvenile (P11–18) HMs. Additionally, mIPSC amplitude distributions were highly variable: CV 0.68 ± 0.05 (means ± SE) for neonates and 0.83 ± 0.06 for juveniles. We wished to ascertain the contribution of glycine receptor (GlyR)-channel properties to this change in quantal amplitude and to the amplitude variability and time course of mIPSCs. To determine whether a postnatal increase in GlyR-channel conductance accounted for the postnatal change in quantal amplitude, the conductance of synaptic GlyR channels was determined by nonstationary variance analysis of mIPSCs. It was 48 ± 8 pS in neonate and 46 ± 10 pS in juvenile HMs, suggesting that developmental changes in mIPSC amplitude do not result from a postnatal alteration of GlyR-channel conductance. Next we determined the open probability ( P open) of GlyR channels in outside-out patches excised from HMs to estimate the contribution of stochastic channel behavior to quantal amplitude variability. Brief (1 ms) pulses of glycine (1 mM) elicited patch currents that closely resembled mIPSCs. The GlyR channels’ P open, calculated by nonstationary variance analysis of these currents, was ∼0.70 (0.66 ± 0.09 in neonates and 0.72 ± 0.05 in juveniles). The decay rate of patch currents elicited by brief application of saturating concentrations of glycine (10 mM) increased postnatally, mimicking previously documented changes in mIPSC time course. Paired pulses of glycine (10 mM) were used to determine if rapid GlyR-channel desensitization contributed to either patch current time course or quantal amplitude variability. Because we did not observe any fast desensitization of patch currents, we believe that fast desensitization of GlyRs underlies neither phenomenon. From our analysis of glycinergic patch currents and mIPSCs, we draw three conclusions. First, channel deactivation is the primary determinant of glycinergic mIPSC time course, and postnatal changes in channel deactivation rate account for observed developmental changes in mIPSC decay rate. Second, because GlyR-channel P openis high, differences in receptor number between synapses rather than stochastic channel behavior are likely to underlie the majority of quantal variability seen at glycinergic synapses throughout postnatal development. We estimate the number of GlyRs available at a synapse to be on average 27 in neonate neurons and 39 in juvenile neurons. Third, this change in the calculated number of GlyRs at each synapse may account for the postnatal increase in mIPSC amplitude.
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Best, Tyler K., Lesley Marson, Karl B. Thor, and Edward C. Burgard. "Synaptic activation of bulbospongiosus motoneurons via dorsal gray commissural inputs." Journal of Neurophysiology 109, no. 1 (January 1, 2013): 58–67. http://dx.doi.org/10.1152/jn.00752.2012.
Full textAbstract:
Ejaculation is controlled by coordinated and rhythmic contractions of bulbospongiosus (BSM) and ischiocavernosus muscles. Motoneurons that innervate and control BSM contractions are located in the dorsomedial portion of the ventral horn in the L5–6 spinal cord termed the dorsomedial (DM) nucleus. We characterized intrinsic properties of DM motoneurons as well as synaptic inputs from the dorsal gray commissure (DGC). Electrical stimulation of DGC fibers elicited fast inhibitory and excitatory responses. In the presence of glutamate receptor antagonists, both fast GABAergic as well as glycinergic inhibitory postsynaptic potentials (IPSPs) were recorded. No slow GABAB-mediated inhibition was evident. In the presence of GABAA and glycine receptor antagonists, DGC stimulation elicited fast glutamatergic excitatory responses that were blocked by application of CNQX. Importantly, a slow depolarization (timescale of seconds) was routinely observed that sufficiently depolarized the DM motoneurons to fire “bursts” of action potentials. This slow depolarization was elicited by a range of stimulus train frequencies and was insensitive to glutamate receptor antagonists (CNQX and d-APV). The slow depolarization was accompanied by an increase in membrane resistance with an extrapolated reversal potential near the K+ Nernst potential. It was mediated by the combination of the block of a depolarization-activated K+ current and the activation of a QX-314-sensitive cation current. These results demonstrate that fast synaptic responses in DM motoneurons are mediated primarily by glutamate, GABA, and glycine receptors. In addition, slow nonglutamatergic excitatory postsynaptic potentials (EPSPs), generated through DGC stimulation, can elicit burstlike responses in these neurons.
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Jiang, Chang-Yu, Tsugumi Fujita, and Eiichi Kumamoto. "Synaptic modulation and inward current produced by oxytocin in substantia gelatinosa neurons of adult rat spinal cord slices." Journal of Neurophysiology 111, no. 5 (March 1, 2014): 991–1007. http://dx.doi.org/10.1152/jn.00609.2013.
Full textAbstract:
Cellular mechanisms for antinociception produced by oxytocin in the spinal dorsal horn have not yet been investigated thoroughly. We examined how oxytocin affects synaptic transmission in substantia gelatinosa neurons, which play a pivotal role in regulating nociceptive transmission, by applying the whole-cell patch-clamp technique to the substantia gelatinosa neurons of adult rat spinal cord slices. Bath-applied oxytocin did not affect glutamatergic spontaneous, monosynaptically-evoked primary-afferent Aδ-fiber and C-fiber excitatory transmissions. On the other hand, oxytocin produced an inward current at −70 mV and enhanced GABAergic and glycinergic spontaneous inhibitory transmissions. These activities were repeated with a slow recovery from desensitization, concentration-dependent and mimicked by oxytocin-receptor agonist. The oxytocin current was inhibited by oxytocin-receptor antagonist, intracellular GDPβS, U-73122, 2-aminoethoxydiphenyl borate, but not dantrolene, chelerythrine, dibutyryl cyclic-AMP, CNQX, Ca2+-free and tetrodotoxin, while the spontaneous inhibitory transmission enhancements were depressed by tetrodotoxin. Current-voltage relation for the oxytocin current reversed at negative potentials more than the equilibrium potential for K+, or around 0 mV. The oxytocin current was depressed in high-K+, low-Na+ or Ba2+-containing solution. Vasopressin V1A-receptor antagonist inhibited the oxytocin current, but there was no correlation in amplitude between a vasopressin-receptor agonist [Arg8]vasopressin and oxytocin responses. It is concluded that oxytocin produces a membrane depolarization mediated by oxytocin but not vasopressin-V1A receptors, which increases neuronal activity, resulting in the enhancement of inhibitory transmission, a possible mechanism for antinociception. This depolarization is due to a change in membrane permeabilities to K+ and/or Na+, which is possibly mediated by phospholipase C and inositol 1,4,5-triphosphate-induced Ca2+-release.
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Yue, Hai-Yuan, Tsugumi Fujita, and Eiichi Kumamoto. "Biphasic modulation by galanin of excitatory synaptic transmission in substantia gelatinosa neurons of adult rat spinal cord slices." Journal of Neurophysiology 105, no. 5 (May 2011): 2337–49. http://dx.doi.org/10.1152/jn.00991.2010.
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Although intrathecally administrated galanin modulates nociceptive transmission in a biphasic manner, this has not been fully examined previously. In the present study, the action of galanin on synaptic transmission in the substantia gelatinosa (SG) neurons of adult rat spinal cord slices was examined, using the whole cell patch-clamp technique. Galanin concentration-dependently increased the frequency of spontaneous excitatory postsynaptic current (EPSC; EC50 = 2.0 nM) without changing the amplitude, indicating a presynaptic effect. This effect was reduced in a Ca2+-free, or voltage-gated Ca2+ channel blocker La3+-containing Krebs solution and was produced by a galanin type-2/3 receptor (GalR2/R3) agonist, galanin 2–11, but not by a galanin type-1 receptor (GalR1) agonist, M617. Galanin also concentration-dependently produced an outward current at −70 mV (EC50 = 44 nM), although this appeared to be contaminated by a small inward current. This outward current was mimicked by M617, but not by galanin 2–11. Moreover, galanin reduced monosynaptic Aδ-fiber- and C-fiber-evoked EPSC amplitude; the former reduction was larger than the latter. A similar action was produced by galanin 2–11, but not by M617. Spontaneous and focally evoked inhibitory (GABAergic and glycinergic) transmission was unaffected by galanin. These findings indicate that galanin at lower concentrations enhances the spontaneous release of l-glutamate from nerve terminals by Ca2+ entry from the external solution following GalR2/R3 activation, whereas galanin at higher concentrations also produces a membrane hyperpolarization by activating GalR1. Moreover, galanin reduces l-glutamate release onto SG neurons from primary afferent fibers by activating GalR2/R3. These effects could partially contribute to the behavioral effect of galanin.
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Gao, Fan, and Samuel M. Wu. "Characterization of Spontaneous Inhibitory Synaptic Currents in Salamander Retinal Ganglion Cells." Journal of Neurophysiology 80, no. 4 (October 1, 1998): 1752–64. http://dx.doi.org/10.1152/jn.1998.80.4.1752.
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Gao, Fan and Samuel M. Wu. Characterization of spontaneous inhibitory synaptic currents in salamander retinal ganglion cells. J. Neurophysiol. 80: 1752–1764, 1998. Spontaneous and light-evoked postsynaptic currents (sPSCs and lePSCs, respectively) in retinal ganglion cells of the larval tiger salamander were recorded under voltage-clamp conditions from living retinal slices. The focus of this study is to characterize the spontaneous inhibitory PSCs (sIPSCs) and their contribution to the light-evoked inhibitory PSCs (leIPSCs) in on-off ganglion cells. sIPSCs were isolated from spontaneous excitatory PSCs (sEPSCs) by application of 10 μM 6,7-dinitroquinoxaline-2,3-dione (DNQX) + 50 μM 2-amino-5-phosphonopentanoic acid (AP5). In ∼70% of on-off ganglion cells, bicuculline (or picrotoxin) completely blocks sIPSCs, suggesting all sIPSCs in these cells are mediated by GABAergic synaptic vesicles and γ-aminobutyric acid-A (GABAA) receptors (GABAergic sIPSCs, or GABAsIPSCs). In the remaining 30% of on-off ganglion cells, bicuculline (or picrotoxin) blocks 70–98% of the sIPSCs, and the remaining 2–30% are blocked by strychnine (glycinergic sIPSCs, or GLYsIPSCs). GABAsIPSCs occur randomly with an exponentially distributed interval probability density function, and they persist without noticeable rundown over time. The GABAsIPSC frequency is greatly reduced by cobalt, consistent with the idea that they are largely mediated by calcium-dependent vesicular release. GABAsIPSCs in DNQX + AP5 are tetrodotoxin (TTX) insensitive, suggesting that amacrine cells that release GABA under these conditions do not generate spontaneous action potentials. The average GABAsIPSCs exhibited linear current-voltage relation with a reversal potential near the chloride equilibrium potential, and an average peak conductance of 319.67 ± 252.83 (SD) pS. For GLYsIPSCs, the average peak conductance increase is 301.68 ± 94.34 pS. These parameters are of the same order of magnitude as those measured in inhibitory miniature postsynaptic currents (mIPSCs) associated with single synaptic vesicles in the CNS. The amplitude histograms of GABAsIPSCs did not exhibit multiple peaks, suggesting that the larger events are not discrete multiples of elementary events (or quanta). We propose that each GABAsIPSC or GLYsIPSC in retinal ganglion cells is mediated by a single or synchronized multiple of synaptic vesicles with variable neurotransmitter contents. In a sample of 16 on-off ganglion cells, the average peak leIPSC (held at 0 mV) at the light onset is 509.0 ± 233.85 pA and that at the light offset is 529.0 ± 339.88 pA. The approximate number of GABAsIPSCs and GLYsIPSCs required to generate the average light responses, calculated by the ratio of the charge (area under current traces) of the leIPSCs to that of the average single sIPSCs, is 118 ± 52 for the light onset, and 132 ± 76 for the light offset.
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Taylor, W. Rowland, Scott Mittman, and David R. Copenhagen. "Passive electrical cable properties and synaptic excitation of tiger salamander retinal ganglion cells." Visual Neuroscience 13, no. 5 (September 1996): 979–90. http://dx.doi.org/10.1017/s0952523800009202.
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AbstractThe passive electrical properties of 17 ON-OFF retinal ganglion cells were derived from electrophysiological recordings. The parameters for each cells' equivalent model were obtained from the transient current responses to small step changes in clamp potential. Thirteen of the cells could be adequately approximated by a spherical soma connected to an equivalent dendritic cable. Estimates for the cell input conductance (GN), membrane time constant (τm), the dendritic-to-soma conductance ratio (ρ), and the normalized electrotonic length (L) were obtained (mean ± standard deviation, n = 13): GN = 580 ± 530 pS, τm = 97 ±72 ms, ρ = 2.8 ± 2.8, and L = 0.34 ± 0.13. Series resistance averaged 32 ± 11 MΩ The mean of the derived soma diameters was 18 ± 6 μm and the mean diameter and length of the equivalent cables were 1.4 ± 0.6 and 470 ± 90 μm, respectively. The average of the specific membrane conductances, 1.67 ± 1.08 S/cm2, corresponded to a membrane resistivity of 60 kΩ-cm2. Computer simulations of synaptic inputs were performed on a representative model, with an electrode at the soma and using the worst-case configuration, in which all synaptic inputs were confined to the tips of the dendrites. We draw three conclusions from the modeling: (1) Under voltage clamp, fast, spontaneous EPSCs would be significantly attenuated and slowed while the time course of the slower, light-evoked non-NMDA and NMDA EPSCs would be minimally distorted by dendritic filtering. (2) Excitatory synaptic reversal potentials can be accurately determined under voltage clamp. (3) In the absence of GABAergic and glycinergic inhibition, the efficacy at the soma of excitatory conductance changes is essentially independent of their dendritic location. The specific membrane resistivity appears to represent a good compromise between having a small membrane time constant and minimal EPSP attenuation.
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Wang, Peiyuan, and Malcolm M. Slaughter. "Effects of GABA Receptor Antagonists on Retinal Glycine Receptors and on Homomeric Glycine Receptor Alpha Subunits." Journal of Neurophysiology 93, no. 6 (June 2005): 3120–26. http://dx.doi.org/10.1152/jn.01228.2004.
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Glycinergic and GABAergic inhibition are juxtaposed at one retinal synaptic layer yet likely perform different functions. These functions have usually been evaluated using receptor antagonists. In examining retinal glycine receptors, we were surprised to find that commonly used concentrations of GABA antagonists blocked significant fractions of the glycine current. In retinal amacrine and ganglion cells, the competitive GABAA receptor antagonists (bicuculline and SR95531) were also competitive GlyR antagonists. Picrotoxinin produced a noncompetitive inhibition of retinal GlyRs. [1,2,5,6-tetrahydropyridine-4-yl] methylphosphinic acid, the GABACR antagonist, did not inhibit glycine receptors. All three GABAA receptor antagonists were competitive inhibitors of homomeric α1 or α2 GlyRs expressed in human embryonic kidney cells (HEK293) cells. Interestingly, bicuculline was much more effective at α2 GlyRs and might be used to separate glycine receptor subtypes. Thus commonly used concentrations of GABA antagonists do not unambiguously differentiate GABA and glycine pathways. Picrotoxinin inhibition of GABAC receptors requires two amino acids in the second transmembrane region (TM2): 2′ serine and 6′ threonine. Although TM2 regions in GABA and glycine receptors are highly homologous, neither 2′ serine nor 6′ threonine is essential for picrotoxinin sensitivity in glycine receptors.
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van Brederode, Johannes F. M., and Albert J. Berger. "Spike-Firing Resonance in Hypoglossal Motoneurons." Journal of Neurophysiology 99, no. 6 (June 2008): 2916–28. http://dx.doi.org/10.1152/jn.01037.2007.
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During an inspiration the output of hypoglossal (XII) motoneurons (HMs) in vitro is characterized by synchronous oscillatory firing in the 20- to 40-Hz range. To maintain synchronicity it is important that the cells fire with high reliability and precision. It is not known whether the intrinsic properties of HMs are tuned to maintain synchronicity when stimulated with time-varying inputs. We intracellularly recorded from HMs in an in vitro brain stem slice preparation from juvenile mice. Cells were held at or near spike threshold and were stimulated with steady or swept sine-wave current functions (10-s duration; 0- to 40-Hz range). Peristimulus time histograms were constructed from spike times based on threshold crossings. Synaptic transmission was suppressed by including blockers of GABAergic, glycinergic, and glutamatergic neurotransmission in the bath solution. Cells responded to sine-wave stimulation with bursts of action potentials at low (<3- to 5-Hz) sine-wave frequency, whereas they phase-locked 1:1 to the stimulus at intermediate frequencies (3–25 Hz). Beyond the 1:1 frequency range cells were able to phase-lock to subharmonics (1:2, 1:3, or 1:4) of the input frequency. The 1:1 phase-locking range increased with increasing stimulus amplitude and membrane depolarization. Reliability and spike-timing precision were highest when the cells phase-locked 1:1 to the stimulus. Our findings suggest that the coding of time-varying inspiratory synaptic inputs by individual HMs is most reliable and precise at frequencies that are generally lower than the frequency of the synchronous inspiratory oscillatory activity recorded from the XII nerve.
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Bertrand, Sandrine, and Jean-René Cazalets. "Postinhibitory Rebound During Locomotor-Like Activity in Neonatal Rat Motoneurons In Vitro." Journal of Neurophysiology 79, no. 1 (January 1, 1998): 342–51. http://dx.doi.org/10.1152/jn.1998.79.1.342.
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Bertrand, Sandrine and Jean-René Cazalets. Postinhibitory rebound during locomotor-like activity in neonatal rat motoneurons in vitro. J. Neurophysiol. 79: 342–351, 1998. The aim of this study was to establish how a membrane property contributes to the neuronal discharge during ongoing behavior. We therefore studied the role of the postinhibitory rebound (PIR) in the bursting discharge of lumbar motoneurons intracellularly recorded in newborn rat in vitro brain stem/spinal cord preparation. The PIR is a transient depolarization that occurs after a hyperpolarization. We first investigated how it was expressed during experimentally induced hyperpolarizations. Its amplitude increased with the inhibition and was voltage dependent. The Ca2+ channel blockers Mn2+ and Co2+ partly suppressed the PIR in a few of the motoneurons tested. When hyperpolarized, the motoneurons exhibited a sag that was associated with the PIR. Adding caesium to the bath abolished both sag and rebound, which suggested that the PIR in the lumbar motoneurons was mainly due to the activation of the inward rectifying current I Q. In the second part, we studied the physiological involvement of PIR during fictive locomotion induced by bath application of N-methyl-d-l-aspartate and serotonin. We established that experimentally induced PIR could initiate or modulate the bursting discharge of motoneurons during fictive locomotion. We then studied whether the firing patterns of the motoneurons were correlated in one way with the synaptic inhibition. When the monosynaptic inhibitory input to the motoneurons was abolished with the glycinergic blocker strychnine, these neurons stopped discharging (although they still were depolarized rhythmically). The firing of action potentials was restored by applying negative current pulses. This study provides evidence as to how one membrane property in mammals is involved in a complex type of behavior, namely locomotion.
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Sanchez, Antonio, Sanda Mustapic, Edward J. Zuperku, Astrid G. Stucke, Francis A. Hopp, and Eckehard A. E. Stuth. "Role of Inhibitory Neurotransmission in the Control of Canine Hypoglossal Motoneuron Activity In Vivo." Journal of Neurophysiology 101, no. 3 (March 2009): 1211–21. http://dx.doi.org/10.1152/jn.90279.2008.
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Hypoglossal motoneurons (HMNs) innervate all tongue muscles and are vital for maintenance of upper airway patency during inspiration. The relative contributions of the various synaptic inputs to the spontaneous discharge of HMNs in vivo are incompletely understood, especially at the cellular level. The purpose of this study was to determine the role of endogenously activated GABAAand glycine receptors in the control of the inspiratory HMN (IHMN) activity in a decerebrate dog model. Multibarrel micropipettes were used to record extracellular unit activity of individual IHMNs during local antagonism of GABAAreceptors with bicuculline and picrotoxin or glycine receptors with strychnine. Only bicuculline had a significant effect on peak and average discharge frequency and on the slope of the augmenting neuronal discharge pattern. These parameters were increased by 30 ± 7% ( P < 0.001), 30 ± 8% ( P < 0.001), and 25 ± 7% ( P < 0.001), respectively. The effects of picrotoxin and strychnine on the spontaneous neuronal discharge and its pattern were negligible. Our data suggest that bicuculline-sensitive GABAergic, but not picrotoxin-sensitive GABAergic or glycinergic, inhibitory mechanisms actively attenuate the activity of IHMNs in vagotomized decerebrate dogs during hyperoxic hypercapnia. The pattern of GABAergic attenuation of IHMN discharge is characteristic of gain modulation similar to that in respiratory bulbospinal premotor neurons, but the degree of attenuation (∼25%) is less than that seen in bulbospinal premotor neurons (∼60%). The current studies only assess effects on active neuron discharge and do not resolve whether the lack of effect of picrotoxin and strychnine on IHMNs also extends to the inactive expiratory phase.
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Barthel, Franziska, Andrea Urban, Lukas Schlösser, Volker Eulenburg, Robert Werdehausen, Timo Brandenburger, Carmen Aragon, Inge Bauer, and Henning Hermanns. "Long-term Application of Glycine Transporter Inhibitors Acts Antineuropathic and Modulates Spinal N-methyl-d-aspartate Receptor Subunit NR-1 Expression in Rats." Anesthesiology 121, no. 1 (July 1, 2014): 160–69. http://dx.doi.org/10.1097/aln.0000000000000203.
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Abstract Background: Dysfunction of spinal glycinergic neurotransmission is a major pathogenetic factor in neuropathic pain. The synaptic glycine concentration is controlled by the two glycine transporters (GlyT) 1 and 2. GlyT inhibitors act antinociceptive in various animal pain models when applied as bolus. Yet, in some studies, severe neuromotor side effects were reported. The aim of the current study was to elucidate whether continuous inhibition of GlyT ameliorates neuropathic pain without side effects and whether protein expression of GlyT1, GlyT2, or N-methyl-d-aspartate receptor subunit NR-1 in the spinal cord is affected. Methods: In the chronic constriction injury model of neuropathic pain, male Wistar rats received specific GlyT1 and GlyT2 inhibitors (ALX5407 and ALX1393; Sigma-Aldrich®, St. Louis, MO) or vehicle for 14 days via subcutaneous osmotic infusion pumps (n = 6). Mechanical allodynia and thermal hyperalgesia were assessed before, after chronic constriction injury, and every 2 days during substance application. At the end of behavioral assessment, the expression of GlyT1, GlyT2, and NR-1 in the spinal cord was determined by Western blot analysis. Results: Both ALX5407 and ALX1393 ameliorated thermal hyperalgesia and mechanical allodynia in a time- and dose-dependent manner. Respiratory or neuromotor side effects were not observed. NR-1 expression in the ipsilateral spinal cord was significantly reduced by ALX5407, but not by ALX1393. The expression of GlyT1 and GlyT2 remained unchanged. Conclusions: Continuous systemic inhibition of GlyT significantly ameliorates neuropathic pain in rats. Thus, GlyT represent promising targets in pain research. Modulation of N-methyl-d-aspartate receptor expression might represent a novel mechanism for the antinociceptive action of GyT1 inhibitors.
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Umemiya, M., and A. J. Berger. "Presynaptic inhibition by serotonin of glycinergic inhibitory synaptic currents in the rat brain stem." Journal of Neurophysiology 73, no. 3 (March 1, 1995): 1192–201. http://dx.doi.org/10.1152/jn.1995.73.3.1192.
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1. With the use of a thin brain stem slice preparation, we recorded in visualized neonatal rat hypoglossal motoneurons unitary glycinergic inhibitory postsynaptic currents (IPSCs) that were evoked by extracellular stimulation of nearby interneurons. We found that 10 microM serotonin (5-HT) presynaptically inhibited this glycinergic synaptic transmission by 85.5%. 2. In the somata of presynaptic interneurons, 5-HT1A receptor activation potentiated inwardly rectifying K+ channels and inhibited voltage-activated calcium channels. 3. In contrast, the 5-HT1B receptor was primarily responsible for inhibition of evoked glycinergic IPSCs; a selective 5-HT1B receptor agonist, N-(3-trifluoromethylphenyl)piperazine (TFMPP, 10 microM), inhibited synaptic transmission by 97.3%. On the other hand, 5-HT1A receptor activation by (+)-8-OH-dipropylaminotetralin (8-OHDPAT, 1 microM) inhibited IPSCs by only 24.1%. A 5-HT1A antagonist, 1-(2-methyoxyphenyl)-4-[4-(2-phthalimido)-butyl]piperazine hydrobromide (NAN-190, 1 microM), had no effect on synaptic inhibition by 5-HT. 4. In the presence of tetrodotoxin (TTX) as well as TTX with cadmium (50 microM), we found that 5-HT1B receptor activation by TFMPP reduced the frequency of spontaneous miniature IPSCs (mIPSCs) without changing their mean amplitude. The results suggested that the 5-HT1B receptors activated at the presynaptic terminal inhibited synaptic transmission independent of inhibiting calcium influx through voltage-activated calcium channels. 5. These results indicate that activation of inwardly rectifying K+ channels and inhibition of voltage-activated calcium channels by 5-HT1A receptor activation do not constitute a main pathway for presynaptic inhibition by 5-HT of glycinergic synaptic transmission.(ABSTRACT TRUNCATED AT 250 WORDS)
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Oleskevich, Sharon, Francisco J. Alvarez, and Bruce Walmsley. "Glycinergic Miniature Synaptic Currents and Receptor Cluster Sizes Differ Between Spinal Cord Interneurons." Journal of Neurophysiology 82, no. 1 (July 1, 1999): 312–19. http://dx.doi.org/10.1152/jn.1999.82.1.312.
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The structural features of a synaptic connection between central neurons play an important role in determining the strength of the connection. In the present study, we have examined the relationship between the structural and functional properties of glycinergic synapses in the rat spinal cord. We have analyzed the structure of glycinergic receptor clusters on rat ventral horn interneurons using antibodies against the glycine receptor clustering protein, gephyrin. We have examined the properties of quantal glycinergic currents generated at these synapses using whole cell patch-clamp recordings of miniature postsynaptic inhibitory currents (mIPSCs) in rat spinal cord slices in vitro. Our immunolabeling results demonstrate that there is a considerable variability in the size of glycine receptor clusters within individual neurons. Furthermore there are large differences in the mean cluster size between neurons. These observations are paralleled closely by recordings of glycinergic mIPSCs. The mIPSC amplitude varies significantly within and between neurons. Results obtained using combined immunolabeling and electrophysiological recording on the same neurons show that cells with small glycine receptor clusters concurrently exhibit small mIPSCs. Our results suggest that the differences in the size of glycinergic receptor clusters may constitute an important factor contributing to the observed differences in mIPSC amplitude among spinal cord interneurons.
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Sebe, Joy Y., Erika D. Eggers, and Albert J. Berger. "Differential Effects of Ethanol on GABAA and Glycine Receptor-Mediated Synaptic Currents in Brain Stem Motoneurons." Journal of Neurophysiology 90, no. 2 (August 2003): 870–75. http://dx.doi.org/10.1152/jn.00119.2003.
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Ethanol potentiates glycinergic synaptic transmission to hypoglossal motoneurons (HMs). This effect on glycinergic transmission changes with postnatal development in that juvenile HMs (P9–13) are more sensitive to ethanol than neonate HMs (P1–3). We have now extended our previous study to investigate ethanol modulation of synaptic GABAA receptors (GABAARs), because both GABA and glycine mediate inhibitory synaptic transmission to brain stem motoneurons. We tested the effects of ethanol on GABAergic and glycinergic miniature inhibitory postsynaptic currents (mIPSCs) recorded from neonate and juvenile rat HMs in an in vitro slice preparation. Bath application of 30 mM ethanol had no significant effect on the GABAergic mIPSC amplitude or frequency recorded at either age. At 100 mM, ethanol significantly decreased the GABAergic mIPSC amplitude recorded from neonate (6 ± 3%, P < 0.05) and juvenile (16 ± 3%, P < 0.01) HMs. The same concentration of ethanol increased the GABAergic mIPSC frequency recorded from neonate (64 ± 17%, P < 0.05) and juvenile (40 ± 15%, n.s.) HMs. In contrast, 100 mM ethanol robustly potentiated glycinergic mIPSC amplitude in neonate (31 ± 3%, P < 0.0001) and juvenile (41 ± 7%, P < 0.001) HMs. These results suggest that glycine receptors are more sensitive to modulation by ethanol than GABAA receptors and that 100 mM ethanol has the opposite effect on GABAAR-mediated currents in juvenile HMs, that is, inhibition rather than enhancement. Further, comparing ethanol's effects on GABAergic mIPSC amplitude and frequency, ethanol modulates GABAergic synaptic transmission to HMs differentially. Presynaptically, ethanol enhances mIPSC frequency while postsynaptically it decreases mIPSC amplitude.
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Pedroarena, Christine M., and Susanne Kamphausen. "Glycinergic synaptic currents in the deep cerebellar nuclei." Neuropharmacology 54, no. 5 (April 2008): 784–95. http://dx.doi.org/10.1016/j.neuropharm.2007.12.005.
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Awatramani, Gautam B., Rostislav Turecek, and Laurence O. Trussell. "Staggered Development of GABAergic and Glycinergic Transmission in the MNTB." Journal of Neurophysiology 93, no. 2 (February 2005): 819–28. http://dx.doi.org/10.1152/jn.00798.2004.
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Maturation of some brain stem and spinal inhibitory systems is characterized by a shift from GABAergic to glycinergic transmission. Little is known about how this transition is expressed in terms of individual axonal inputs and synaptic sites. We have explored this issue in the rat medial nucleus of the trapezoid body (MNTB). Synaptic responses at postnatal days 5–7 (P5–P7) were small, slow, and primarily mediated by GABAA receptors. By P8–P12, an additional, faster glycinergic component emerged. At these ages, GABAA, glycine, or both types of receptors mediated transmission, even at single synaptic sites. Thereafter, glycinergic development greatly accelerated. By P25, evoked inhibitory postsynaptic currents (IPSCs) were 10 times briefer and 100 times larger than those measured in the youngest group, suggesting a proliferation of synaptic inputs activating fast-kinetic receptors. Glycinergic miniature IPSCs (mIPSCs) increased markedly in size and decay rate with age. GABAergic mIPSCs also accelerated, but declined slightly in amplitude. Overall, the efficacy of GABAergic inputs showed little maturation between P5 and P20. Although gramicidin perforated-patch recordings revealed that GABA or glycine depolarized P5–P7 cells but hyperpolarized P14–P15 cells, the young depolarizing inputs were not suprathreshold. In addition, vesicle-release properties of inhibitory axons also matured: GABAergic responses in immature rats were highly asynchronous, while in older rats, precise, phasic glycinergic IPSCs could transmit even with 500-Hz stimuli. Thus development of inhibition is characterized by coordinated modifications to transmitter systems, vesicle release kinetics, Cl− gradients, receptor properties, and numbers of synaptic inputs. The apparent switch in GABA/glycine transmission was predominantly due to enhanced glycinergic function.
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Wang, Jijiang, Xin Wang, Mustapha Irnaten, Priya Venkatesan, Cory Evans, Sunit Baxi, and David Mendelowitz. "Endogenous Acetylcholine and Nicotine Activation Enhances GABAergic and Glycinergic Inputs to Cardiac Vagal Neurons." Journal of Neurophysiology 89, no. 5 (May 1, 2003): 2473–81. http://dx.doi.org/10.1152/jn.00934.2002.
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The heart slows during expiration and heart rate increases during inspiration. This cardiorespiratory interaction is thought to occur by increased inhibitory synaptic events to cardiac vagal neurons during inspiration. Since cholinergic receptors have been suggested to be involved in this cardiorespiratory interaction, we tested whether endogenous cholinergic activity modulates GABAergic and glycinergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus, whether nicotine can mimic this facilitation, and we examined the nicotinic receptors involved. Cardiac vagal neurons in the rat were labeled with a retrograde fluorescent tracer and studied in an in vitro slice using patch-clamp techniques. Application of neostigmine (10 μM), an acetylcholinerase inhibitor, significantly increased the frequency of both GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) in cardiac vagal neurons. Exogenous application of nicotine increased the frequency and amplitude of both GABAergic and glycinergic IPSCs. The nicotinic facilitation of both GABAergic and glycinergic IPSCs were insensitive to 100 nM α-bungarotoxin but were abolished by dihydro-β-erythrodine (DHβE) at a concentration (3 μM) specific for α4β2 nicotinic receptors. In the presence of TTX, nicotine increased the frequency of GABAergic and glycinergic miniature synaptic events, which were also abolished by DHβE (3 μM). This work demonstrates that there is endogenous cholinergic facilitation of GABAergic and glycinergic synaptic inputs to cardiac vagal neurons, and activation of α4β2 nicotinic receptors at presynaptic terminals facilitates GABAergic and glycinergic neurotransmission to cardiac vagal neurons. Nicotinic facilitation of inhibitory neurotransmission to premotor cardiac parasympathetic neurons may be involved in generating respiratory sinus arrhythmia.
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Donato, Roberta, and Andrea Nistri. "Relative Contribution by GABA or Glycine to Cl−-Mediated Synaptic Transmission on Rat Hypoglossal Motoneurons In Vitro." Journal of Neurophysiology 84, no. 6 (December 1, 2000): 2715–24. http://dx.doi.org/10.1152/jn.2000.84.6.2715.
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The relative contribution by GABA and glycine to synaptic transmission of motoneurons was investigated using an hypoglossus nucleus slice preparation from neonatal rats. Spontaneous, miniature, or electrically evoked postsynaptic currents (sPSCs, mPSCs, ePSCs, respectively) mediated by glycine or GABA were recorded under whole cell voltage clamp after blocking excitatory glutamatergic transmission with kynurenic acid. The overall majority of Cl−-mediated sPSCs was glycinergic, while only one-third was GABAergic; 70 ± 10% of mPSCs were glycinergic while 22 ± 8% were GABAergic. Tetrodotoxin (TTX) application dramatically reduced the frequency (and slightly the amplitude) of GABAergic events without changing frequency or amplitude of glycinergic sPSCs. These results indicate that, unlike spontaneous GABAergic transmission, glycine-mediated neurotransmission was essentially independent of network activity. There was a consistent difference in the kinetics of GABAergic and glycinergic responses as GABAergic events had significantly slower rise and decay times than glycinergic ones. Such a difference was always present whenever sPSCs, mPSCs, or ePSCs were measured. Finally, GABAergic and glycinergic mPSCs were differentially modulated by activation of glutamate metabotropic receptors (mGluRs), which are abundant in the hypoglossus nucleus. In fact, the broad-spectrum mGluR agonist (±)-1-aminocyclopentane- trans-1,3-dicarboxylic acid (50 μM), which in control solution increased the frequency of both GABAergic and glycinergic sPSCs, enhanced the frequency of glycinergic mPSCs only. These results indicate that on brain stem motoneurons, Cl−-mediated synaptic transmission is mainly due to glycine rather than GABA and that GABAergic and glycinergic events differ in terms of kinetics and pharmacological sensitivity to mGluR activation or TTX.
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Balakrishnan, Veeramuthu, and Laurence O. Trussell. "Synaptic Inputs to Granule Cells of the Dorsal Cochlear Nucleus." Journal of Neurophysiology 99, no. 1 (January 2008): 208–19. http://dx.doi.org/10.1152/jn.00971.2007.
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The mammalian dorsal cochlear nucleus (DCN) integrates auditory nerve input with nonauditory signals via a cerebellar-like granule cell circuit. Although granule cells carry nonauditory information to the DCN, almost nothing is known about their physiology. Here we describe electrophysiological features of synaptic inputs to granule cells in the DCN by in vitro patch-clamp recordings from P12 to P22 rats. Granule cells ranged from 6 to 8 μm in cell body diameter and had high-input resistance. Excitatory postsynaptic currents consisted of both AMPA receptor-mediated and N-methyl-d-aspartate receptor-mediated currents. Synaptically evoked excitatory postsynaptic currents ranged from −25 to −140 pA with fast decay time constants. Synaptic stimulation evoked both short- and long-latency synaptic responses that summated to spike threshold, indicating the presence of a polysynaptic excitatory pathway in the granule cell circuit. Synaptically evoked inhibitory postsynaptic currents in Cl−-loaded cells ranged from −30 to −1,021 pA and were mediated by glycine and, to a lesser extent, GABAA receptors. Unlike cerebellar granule cells, DCN granule cells lacked tonic inhibition by GABA. The glycinergic synaptic conductance was mediated by heteromeric glycine receptors and was far stronger than the glutamatergic conductance, suggesting that glycinergic neurons may act to gate nonauditory signals in the DCN.
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Dieudonne, S. "Glycinergic synaptic currents in Golgi cells of the rat cerebellum." Proceedings of the National Academy of Sciences 92, no. 5 (February 28, 1995): 1441–45. http://dx.doi.org/10.1073/pnas.92.5.1441.
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Gao, Bao-Xi, Christian Stricker, and Lea Ziskind-Conhaim. "Transition From GABAergic to Glycinergic Synaptic Transmission in Newly Formed Spinal Networks." Journal of Neurophysiology 86, no. 1 (July 1, 2001): 492–502. http://dx.doi.org/10.1152/jn.2001.86.1.492.
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The role of glycinergic and GABAergic systems in mediating spontaneous synaptic transmission in newly formed neural networks was examined in motoneurons in the developing rat spinal cord. Properties of action potential–independent miniature inhibitory postsynaptic currents (mIPSCs) mediated by glycine and GABAA receptors (GlyR and GABAAR) were studied in spinal cord slices of 17- to 18-day-old embryos ( E17–18) and 1- to 3-day-old postnatal rats ( P1–3). mIPSC frequency and amplitude significantly increased after birth, while their decay time decreased. To determine the contribution of glycinergic and GABAergic synapses to those changes, GlyR- and GABAAR-mediated mIPSCs were isolated based on their pharmacological properties. Two populations of pharmacologically distinct mIPSCs were recorded in the presence of glycine or GABAA receptors antagonists: bicuculline-resistant, fast-decaying GlyR-mediated mIPSCs, and strychnine-resistant, slow-decaying GABAAR-mediated mIPSCs. The frequency of GABAAR-mediated mIPSCs was fourfold higher than that of GlyR-mediated mIPSCs at E17–18, indicating that GABAergic synaptic sites were functionally dominant at early stages of neural network formation. Properties of GABAAR-mediated mIPSC amplitude fluctuations changed from primarily unimodal skewed distribution at E17–18 to Gaussian mixtures with two to three discrete components at P1–3. A developmental shift from primarily long-duration GABAergic mIPSCs to short-duration glycinergic mIPSCs was evident after birth, when the frequency of GlyR-mediated mIPSCs increased 10-fold. This finding suggested that either the number of glycinergic synapses or the probability of vesicular glycine release increased during the period studied. The increased frequency of GlyR-mediated mIPSCs was associated with more than a twofold increase in their mean amplitude, and in the number of motoneurons in which mIPSC amplitude fluctuations were best fitted by multi-component Gaussian curves. A third subpopulation of mIPSCs was apparent in the absence of glycine and GABAA receptor antagonists: mIPSCs with both fast and slow decaying components. Based on their dual-component decay time and their suppression by either strychnine or bicuculline, we assumed that these were generated by the activation of co-localized postsynaptic glycine and GABAA receptors. The contribution of mixed glycine-GABA synaptic sites to the generation of mIPSCs did not change after birth. The developmental switch from predominantly long-duration GABAergic inhibitory synaptic currents to short-duration glycinergic currents might serve as a mechanism regulating neuronal excitation in the developing spinal networks.
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O’Brien, Jennifer A., and Albert J. Berger. "Cotransmission of GABA and Glycine to Brain Stem Motoneurons." Journal of Neurophysiology 82, no. 3 (September 1, 1999): 1638–41. http://dx.doi.org/10.1152/jn.1999.82.3.1638.
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Using whole cell patch-clamp recording in a rat brain stem slice preparation, we found that γ-aminobutyric acid (GABA) and glycine act as cotransmitters to hypoglossal motoneurons (HMs). Focal application of GABA and glycine onto a single HM revealed that GABAAand glycine receptors are present on the same neuron. To demonstrate that HMs receive both GABAergic and glycinergic synaptic inputs, we simultaneously recorded GABAA- and glycine-receptor–mediated spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in single HMs. GABAergic and glycinergic mIPSCs were differentiated based on their kinetics and modulation by pentobarbital. Specifically, GABAA-receptor–mediated events decayed more slowly than glycine-receptor–mediated events. GABAergic response decay kinetics were prolonged by pentobarbital, whereas glycinergic response decay kinetics remained unchanged. The distinct kinetics of the glycine- and GABAA-receptor-mediated synaptic events allowed us to record dual component mIPSCs, mIPSCs that are mediated by both receptor types. These data suggest that GABA and glycine are colocalized in the same presynaptic vesicle and are coreleased from presynaptic terminals opposed to motoneurons.
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Liu, Tao, Tsugumi Fujita, Terumasa Nakatsuka, and Eiichi Kumamoto. "Phospholipase A2 Activation Enhances Inhibitory Synaptic Transmission in Rat Substantia Gelatinosa Neurons." Journal of Neurophysiology 99, no. 3 (March 2008): 1274–84. http://dx.doi.org/10.1152/jn.01292.2007.
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Phospholipase A2 (PLA2) activation enhances glutamatergic excitatory synaptic transmission in substantia gelatinosa (SG) neurons, which play a pivotal role in regulating nociceptive transmission in the spinal cord. By using melittin as a tool to activate PLA2, we examined the effect of PLA2 activation on spontaneous inhibitory postsynaptic currents (sIPSCs) recorded at 0 mV in SG neurons of adult rat spinal cord slices by use of the whole cell patch-clamp technique. Melittin enhanced the frequency and amplitude of GABAergic and glycinergic sIPSCs. The enhancement of GABAergic but not glycinergic transmission was largely depressed by Na+ channel blocker tetrodotoxin or glutamate-receptor antagonists (6-cyano-7-nitroquinoxaline-2,3-dione and/or dl-2-amino-5-phosphonovaleric acid) and also in a Ca2+-free Krebs solution. The effects of melittin on glycinergic sIPSC frequency and amplitude were dose-dependent with an effective concentration of ∼0.7 μM for half-maximal effect and were depressed by PLA2 inhibitor 4-bromophenacyl bromide or aristolochic acid. The melittin-induced enhancement of glycinergic transmission was depressed by lipoxygenase inhibitor nordihydroguaiaretic acid but not cyclooxygenase inhibitor indomethacin. These results indicate that the activation of PLA2 in the SG enhances GABAergic and glycinergic inhibitory transmission in SG neurons. The former action is mediated by glutamate-receptor activation and neuronal activity increase, possibly the facilitatory effect of PLA2 activation on excitatory transmission, whereas the latter action is due to PLA2 and subsequent lipoxygenase activation and is independent of extracellular Ca2+. It is suggested that PLA2 activation in the SG could enhance not only excitatory but also inhibitory transmission, resulting in the modulation of nociception.
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Leao, Richardson N., Sharon Oleskevich, Hong Sun, Melissa Bautista, Robert E. W. Fyffe, and Bruce Walmsley. "Differences in Glycinergic mIPSCs in the Auditory Brain Stem of Normal and Congenitally Deaf Neonatal Mice." Journal of Neurophysiology 91, no. 2 (February 2004): 1006–12. http://dx.doi.org/10.1152/jn.00771.2003.
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We have investigated the fundamental properties of central auditory glycinergic synapses in early postnatal development in normal and congenitally deaf ( dn/dn) mice. Glycinergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded using patch-clamp methods in neurons from a brain slice preparation of the medial nucleus of the trapezoid body (MNTB), at 12-14 days postnatal age. Our results show a number of significant differences between normal and deaf mice. The frequency of mIPSCs is greater (50%) in deaf versus normal mice. Mean mIPSC amplitude is smaller in deaf mice than in normal mice (mean mIPSC amplitude: deaf, 64 pA; normal, 106 pA). Peak-scaled fluctuation analysis of mIPSCs showed that mean single channel conductance is greater in the deaf mice (deaf, 64 pS; normal, 45 pS). The mean decay time course of mIPSCs is slower in MNTB neurons from deaf mice (mean half-width: deaf, 2.9 ms; normal, 2.3 ms). Light- and electron-microscopic immunolabeling results showed that MNTB neurons from deaf mice have more (30%) inhibitory synaptic sites (postsynaptic gephyrin clusters) than MNTB neurons in normal mice. Our results demonstrate substantial differences in glycinergic transmission in normal and congenitally deaf mice, supporting a role for activity during development in regulating both synaptic structure (connectivity) and the fundamental (quantal) properties of mIPSCs at central glycinergic synapses.