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1
MAURI, MARIO. « Cellule staminali mesenchimali : potenziali modulatori del sistema nervoso centrale ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/39835.
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Bone marrow-derived mesenchymal stem cells (MSCs) account for a small population of cells of the non-hematopoietic component of bone marrow. MSCs are multipotent stem cells endowed with neurotrophic potential combined to immunological properties, making them a promising therapeutic tool for neurodegenerative disorders. Although the mechanisms by which they act are still largely unknown, trans-differentiation, paracrine and autocrine actions have been hypothesized. Here we focus on the study of the effects exerted by rat MSCs on CNS neurons and oligodendrocytes by using a simplified in vitro co-culture system that precludes any direct contact between different cell types.
The analysis of hippocampal synaptogenesis, synaptic vesicle recycling and electrical activity show that MSCs by themselves, efficiently support morphological and functional neuronal differentiation. Our observations demonstrate that MSCs selectively and directly increased hippocampal GABAergic presynapses and inhibitory transmission. In fact, this increment correlated to a higher expression of the potassium/chloride KCC2 cotransporter and to an enhancement of both the frequency and the amplitude of mIPSC and sIPSC. The decreased of GABA synapses following the treatment with a widely used Trk-neurotrophin receptor blocker, K252a, and the more specific TrkB receptor bodies prompt for the involvement of the brain derived neurotrophic factor (BDNF) in mediating such effects. The involvement of this neurotrophin is also strengthened by test ELISA on the culture medium collected from MSC-neuron co-cultures in which an higher BDNF concentration was detected, when compared to astrocyte-neuron co-cultures.
The results obtained indicate that MSC-secreted factors induce glial-dependent neuronal survival and directly trigger an augmented GABAergic transmission in hippocampal cultures, highlighting a new effect by which MSCs could cooperate in CNS repair.
Additionally, MSCs have been described to improve the clinical course of some demyelinating pathologies and to promote tissue repair through immunological mechanisms and neuroprotective effects. Following these evidences we performed in vitro and in vivo experiments to assess whether MSCs exert their actions through the support of oligodendrocytes (OLs), the myelinating CNS cells, and participate in the regulation of their proliferation and maturation. Through the analysis of specific proteins typically used as markers of the different stages of proliferation, maturation and differentiation (specifically, the membrane glycoprotein O4, the proteoglycan NG2 and myelin basic protein MBP, respectively), it has been noticed that MSCs are capable to prolong the proliferation phase of OPCs and also to anticipate OL differentiation, with respect to standard astrocyte/OL co-cultures. Moreover we investigated a possible molecular mechanism underlying these phenomena focusing on neurotrophin pathways. Trk receptors activation was analyzed in order to find out a possible role of neurotrophins in MSC-mediated effects on OLs, as it happens in neuronal cultures. We focused on the changes in the phosphorylation level of ERK (Extracellular signaling-regulated kinases), one of the activated effectors by TrK receptors. Our observations show that, in OLs co-cultured with MSCs, ERK is highly phosphorylated with respect to astrocyte/OL co-cultures, suggesting a MSC-induced activation of the pathways regulated by this protein. These data, although preliminary, suggest that MSCs positively act on the regulation of proliferation and maturation of OLs and, due to the observed effects on the regulation of synaptogenesis (see above), make these cells an interesting model for the identification of molecules involved in MSC neuroprotective processes. This may open new therapeutic approaches in the treatment of neurodegenerative diseases involving not only a synaptic imbalance, as it happens in various forms of epilepsy, but also in demyelinating diseases. Thus, in this research project, we aimed at characterising the molecular mechanisms underlying MSC actions that could participate in the recovery of neurological disorders or demyelinating pathologies.
2
Garden, Derek Leonard Frank. « GABAergic transmission in the perirhinal cortex in vitro ». Thesis, University of Bristol, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274770.
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3
Mellor, Jack Robert. « Electrophysiological investigation of the mechanisms underlying GABAergic synaptic transmission ». Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624122.
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Fan, Kai Yoon. « GABAergic synaptic transmission, plasticity and integration in the subthalamic nucleus ». Thesis, University of Sheffield, 2012. http://etheses.whiterose.ac.uk/3167/.
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Diana, Marco Alberto. « Charakterisierung von einer retrograden Modulation inhibitorischer synaptischer Transmission im Kleinhirn der Ratte ». Doctoral thesis, [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=971021988.
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Asseri, Khalid. « Effects of AMBD and isovaline on GABAergic transmission in thalamic neurons ». Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/35078.
Texte intégralRésumé :
In central neurons, the endogenous amino acid γ-aminobutyric acid (GABA) exerts synaptic inhibition mediated through ionotropic GABAA-, or metabotropic GABAB-receptors. These receptors exist on both pre- and postsynaptic membranes. The synthetic structural analogues of GABA, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide (AMBD) and R-isovaline have received little study on synaptic inhibition in the mammalian thalamus. AMBD was originally proposed as a taurine antagonist whereas R-isovaline is a non-biogenic amino acid that increases postsynaptic K⁺ conductance of thalamocortical neurons. The aim of this work was to assess the prediction that AMBD and R-isovaline would affect presynaptic release of GABA onto neurons of ventrobasal nuclei.
AMBD and R-isovaline were applied by perfusion of thalamic slices obtained from juvenile Sprague-Dawley rats (P10 -13). During whole-cell patch clamp recording from thalamocortical neurons, we voltage-clamped neurons at a holding potential of -70 mV. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded in the presence of tetrodotoxin (TTX). Kynurenic acid and internal Cs⁺ were used to block postsynaptic glutamate receptors and K⁺ conductances. We used the GABAA antagonist bicuculline to identify GABAergic mIPSCs, without affecting a possible presynaptic GABAB-component.
Applied alone at 250 μM, AMBD had no effect on the passive and active membrane properties of neurons. In the range of 10 µM to 1 mM, AMBD had no effect on amplitude or decay time constant of GABAergic mIPSCs. Acting with an IC₅₀ of 232 μM, AMBD reversibly reduced the frequency of GABAergic mIPSCs. The above observations implied that AMBD reduced presynaptic release of GABA. In a range of 25 to 200 µM, R-isovaline had no effect on the holding current or frequency, amplitude and decay time constant of GABAergic mIPSCs. Hence, R-isovaline did not affect release of GABA and did not affect receptors on nerve terminals.
In summary, AMBD reversibly decreased the presynaptic release of GABA, likely by an action on nerve terminals while having no effects on postsynaptic membrane properties that could account for the reduced frequency of GABAergic mIPSCs. The exact mechanism whereby AMBD decreased GABA release remains unclear. R-isovaline had no effect on GABA release in ventrobasal nuclei.
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Cao, Zhiwen, et 曹志文. « GABAergic transmission in developmental establishment of a gravity-related spatial reference ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47151304.
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In rats, the subnuclei of the inferior olive (IO) and thalamus exist
topographic spatial representation to sinusoidal horizontal linear translations along either the antero-posterior or interaural direction. To examine the effect of GABAergic neurotransmission within the vestibular nucleus on the establishment of gravity-related topographic spatial representation in relay station of the central vestibular pathway, GABAA receptor antagonist bicuculline was used to chronically perturb GABA transmission within the vestibular nucleus of postnatal rats. Implantation of bicuculline-loaded or saline-loaded Elvax slice onto the dorsal surface of vestibular nucleus was performed in P1 rats which were allowed to recover into adulthood. Fos protein expression was used as an indicator to identify central neurons responsive to horizontal linear accelerations. In stationary or labyrinthectomized rats, Fos-immunoreactive (ir) neurons were either absent or sporadically scattered throughout the IO and thalamic subnuclei, indicating that the Fos expression in these neural area was otolithic in origin. In the saline control group, Fos expression induced by horizontal antero-posterior linear acceleration was observed in both the IO and thalamus. Responsive IO subnuclei include β subnucleus of IO and dorsomedial cell column while those in the thalamus include central medial nucleus, paracentral nucleus, mediodorsal nucleus, central lateral nucleus, zona incerta and subparafascicular nucleus of thalamus. For-ir neurons responsive to horizontal interaural linear acceleration were found in those IO subnuclei and thalamic subnuclei. When compared with the saline-treated group, the number of Fos-ir IO neurons responsive to horizontal linear acceleration was significantly lower in adult rats perturbed with bicuculline at P1. Besides, the pattern of Fos expression in both the IO and thalamus was altered in adult rats pretreated with bicuculline. In the utricle-related thalamic subnuclei, the postnatal time when Fos-ir neurons were found triggered by otolithic stimulation was delayed and the number of these Fos-ir neurons was fewer in the bicuculline-treated group than those in the saline-treated group. To investigate whether there exists a critical period for postnatal establishment of topographic spatial representation in the IO and thalamus, implantation of bicuculline-loaded Elvax slice onto the vestibular nucleus was carried out in P14 rats. The topographic spatial representation in IO and thalamus of those rats were unchanged as compared with adult rats pretreated with saline at P14. These results indicate that the GABAergic neuronal circuit in the vestibular nucleus plays an important role in postnatal establishment of topographic spatial representation in the central vestibular system. Most importantly, we documented the occurrence of a postnatal critical period (between P1 and P14) during which GABAergic transmission
regulated the formation of a gravity-related spatial framework in the brain.published_or_final_version
Physiology
Master
Master of Philosophy
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Ma, Ying [Verfasser]. « Effects of enhancing GABAergic transmission on sleep-associated memory consolidation / Ying Ma ». Lübeck : Zentrale Hochschulbibliothek Lübeck, 2012. http://d-nb.info/1021331007/34.
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Yuan, Ning. « DISTINCT MODULATORY EFFECTS OF DOPAMINE ON EXCITATORY CHOLINERGIC AND INHIBITORY GABAERGIC SYNAPTIC TRANSMISSION IN DROSOPHILA ». Ohio University / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1149001533.
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Seiscio, Andrew R. « The Role of GABAergic Transmission in Mediation of Striatal Local Field Potentials (LFPs) ». Digital Archive @ GSU, 2008. http://digitalarchive.gsu.edu/psych_theses/63.
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In the present study, electrophysiological and behavioral effects of compromised Gama-Aminobutyric Acid (GABAergic) transmission were investigated in adult Rhesus macaque monkeys (N=2). GABAergic transmission was perturbed in the putamen by administration of a GABAa receptor antagonist, gabazine (10 and 500 μM), via a microdialysis-local field potential (MD-LFP) probe. Resultant changes in striatal local field potentials (LFPs) were measured as an assay of synchrony. Gabazine perfusion evoked discrete large amplitude spikes in LFPs in all subjects, and the frequency and shape of individual spikes were concentration-dependent. Pre-treatment with the GABAa receptor agonist, muscimol (100 μM) blocked the gabazine-induced events, confirming a role for GABAa receptors in the effects. Behavioral manifestations of gabazine treatment were observed only at the maximum concentration. Unusual facial movements suggested aberrant electrical activity was propagated from striatum to motor cortex, perhaps via reentrant circuits. These results support a role for GABAergic transmission in segregation of striatal circuits.
11
Ng, Ka-pak, et 吳嘉白. « Glutamatergic and GABAergic transmission regulate the maturation of vestibular circuitry for spatial recognition ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45200312.
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Piantadosi, Patrick Thomas. « Modulation of fear-related behaviors by prefrontal cortical GABAergic transmission and its relevance to schizophrenia ». Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44818.
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Individuals with schizophrenia are hypothesized to have a “noisy” prefrontal cortex (PFC), resulting from deficient gamma-aminobutyric acid (GABA) inhibitory neurotransmission. Given that the PFC regulates emotional functioning, it is possible that neuropathological alterations in PFC GABA function contribute to deficits in affective functioning in schizophrenia. In particular, schizophrenic patients have been suggested to apply aberrant motivational salience to cues, often being hyporesponsive to cues that predict reinforcement, and hyperresponsive to cues that do not predict reward. These types of deficits can be assessed in non-human animals using discriminative Pavlovian fear conditioning and latent inhibition paradigms. In the present study, experiments were conducted to elucidate the role of PFC GABAergic transmission in the allocation of motivational salience to conditioned stimuli. Animals were trained to lever press for sucrose reward, after which fear was assessed (using conditioned suppression of lever pressing) on one of the two aversive conditioning paradigms conducted. Saline infused control animals showed normal application of motivational salience, characterized by adaptive discrimination between aversive (CS+) and neutral cues (CS-) during discriminative Pavlovian fear conditioning, and acquired irrelevance to a stimuli that was preexposed during latent inhibition. Pharmacological blockade of GABAA-receptors prior to the conditioning or test phase of the discriminative fear task eliminiated the ability to behaviorally discriminate between a CS+ and CS-. Interestingly, only pre-conditioning infusions resulted in elevated fear to the CS-, suggesting that abnormal hyperresponsivity to a neutral cue is related to deficient GABA function during acquisition, but not recall. Blockade of GABAA-receptors prior to conditioning had no effect on latent inhibition, but did enhance fear in animals that were non-preexposed to the conditioned stimulus. In contrast, latent inhibition was abolished following GABA-blockade prior to the test phase of the task. Taken together, these deficits suggest that PFC GABA transmission is critical for adaptive behavior following aversive conditioning. Such deficits observed in schizophrenia may be causally related to PFC GABA deficiency, predisposing these individuals to aberrant attributions of motivational salience to environmental stimuli.
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Gabrielli, M. « ACTIVE ENDOCANNABINOIDS ARE RELEASED FROM MICROGLIA IN ASSOCIATION WITH EXTRACELLULAR VESICLES TO INHIBIT GABAERGIC TRANSMISSION ». Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/346707.
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Endocannabinoids (eCBs) are bioactive lipids which primarily influence synaptic communication within the nervous system. They are synthesized by neurons but also by microglia, especially under neuroinflammatory conditions. To exert their function, eCBs travel across the intercellular space. However, how eCBs move extracellularly remains obscure. Our recent evidence indicates that reactive microglia release extracellular vesicles (EVs), which may represent an ideal vehicle for the transport of hydrophobic eCBs. Hence, in this study we investigated whether microglial EVs carry eCBs and may influence neurotransmission.
First we analyzed the eCB content of EVs and found a clear enrichment of N-arachidonoylethanolamine (AEA) in EVs relative to parental microglia. This analysis revealed higher AEA levels in EVs shed from the plasma membrane (microvesicles), compared to those which originate from the endocytic compartment (exosomes). To bioassay the activity of vesicular AEA, we used patch clamp analysis of miniature inhibitory post-synaptic currents (mIPSC) on rat hippocampal primary culture. Exposure of neurons to microvesicles (MVs) induced a significant decrease in mIPSC frequency, mimicking the well-known inhibitory action of CB1 receptor agonists. The involvement of vesicular AEA in this phenomenon was inferred from the ability of the CB1 receptor antagonist SR141716A to block the reduction of mIPSC frequency evoked by MVs. Western blot analysis showed an increase in ERK phosphorylation in neurons exposed to MVs, which was completely inhibited by SR141716A. This indicate that CB1 receptors activation by AEA-storing MVs translates into downstream signaling.
Finally, the use of biotin-AEA revealed an affinity of AEA for MV membrane, indicating that AEA travels in association with MVs surface. Consistent with a surface localization of AEA, MV membranes maintain their capability to decrease mIPSC frequency.
Overall, this study shows that microglial MVs carry AEA on their surface to stimulate CB1 receptors on target GABAergic neurons and demonstrates that extracellular vesicular transport of eCBs play a crucial role in the modulation of inhibitory transmission.
This abstract is copyrighted
© 2015 Gabrielli et al
SpringerPlus 2015, 4(Suppl 1):L29 doi:10.1186/2193-1801-4-S1-L29, modified;
The electronic version of this abstract is the complete one and can be found online at: http://www.springerplus.com/content/4/S1/L29
This abstract is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Ayling, Martin D. T. « A computational analysis of the functional role of GABAergic synaptic transmission in striatal medium spiny neurons ». Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491856.
Texte intégralRésumé :
Medium Spiny projection neurons, the sole output neurons of the striatum, are connected by GABAergic synapses. Such connections are classically assumed to be inhibitory, thus it has been suggested that one of the main functions of the striatum is to detect and classify cortical representations of sensory events to trigger appropriate motor responses through a winner-take-all network dynamic.
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Zheng, Thomas Wen-Juan. « Neurophysiological and pharmacological study of carbamazepine on physiological and pathological GABAergic-dependent thalamocortical oscillations ». Strasbourg, 2010. http://www.theses.fr/2010STRA6131.
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La CBZ est un anticonvulsivant largement prescrit, utilisé dans le traitement des épilepsies focales et de troubles psychiatriques. Cependant, il est connu que son large spectre d'action sur différentes cibles moléculaires contribue à des effets secondaires communs et sévères. La CBZ interagit directement avec les récepteurs GABAA, qui jouent un rôle critique dans l’électrogenèse d’oscillations TC/CT physiologiques et pathologiques. Mon travail de thèse offre des arguments solides pour dire que la CBZ module les propriétés de décharge et d’oscillations des neurones thalamiques, au moins dans le système somatosensoriel, au travers d’une augmentation des activités dépendantes de récepteurs GABAA. Ce mécanisme semble être le plus vraisemblable dans l’aggravation des absences. Le travail présenté dans cette thèse offre aussi d’importantes clés pour comprendre les mécanismes sous-tendant l'initiation et la propagation des DPO liées aux absences. Ces résultats mettent en évidence la présence d'activités de type précurseur dans S2 et IC durant l’électrogenèse des DPO. Il est donc tentant de mettre en avant l'hypothèse selon laquelle les aires corticales S2 et IC forment un circuit critique à partir duquel une excitation se propage dans des aires corticales interconnectées : S1, des aires corticales motrice et plus frontales. La propagation de cette excitation caudo-rostral pourrait être un élément neuronal clé dans l'initiation des crises d'absences. La CBZ est efficace chez les GAERS pour supprimer les DPO relatives aux absences uniquement lors d'une injection proche ou au niveau du site d'initiation présumé de cet embrasement excitateur caudo-rostralCBZ is a widely prescribed anticonvulsant used for the treatment of focal epilepsy and psychiatric disorders. However it is also known for its broad spectrum of action on several molecular targets contributing to common and severe side effects. CBZ directly interacts with GABAA receptors, which play a critical role in the generation of physiological and pathological TC/CT oscillations. My thesis work provides strong evidence that CBZ affects the firing and oscillation properties of thalamic neurons, at least in the somatosensory system, through enhancement of GABAA receptor-mediated activities, the likely mechanisms that underlie the aggravation of absence seizures. The work presented in this thesis also provides several important leads to mechanisms underlying the initiation and propagation of absence-related SWDs. The present findings demonstrate the presence of precursor cellular and network rhythmic activities in S2 and IC during the generation of absence-related SWDs. Therefore it is tempting to put forward the assumption that S2 and IC cortical areas contain a critical circuit from which excitation spreads to interconnected S1, motor and more frontal cortical areas. This spreading caudo-rostral excitation might be a key neuronal mechanism in the initiation of absence seizures. To all appearances CBZ is effective in suppressing absence-related SWDs
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Motsumori, Tomoyuki. « Thromboxane receptor activation enhances striatal dopamine release, leading to suppression of GABAergic transmission and enhanced sugar intake ». Kyoto University, 2012. http://hdl.handle.net/2433/152495.
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SAVARDI, ANNALISA. « Discovery and Characterization of Novel Selective NKCC1 Inhibitors for Down Syndrome and Brain Disorders with Depolarizing GABAergic Transmission ». Doctoral thesis, Università degli studi di Genova, 2019. http://hdl.handle.net/11567/939823.
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Proper GABAergic transmission through Cl-permeable GABAA receptors is fundamental for physiological brain development and function. Indeed, defective GABAergic signaling -due to a high ratio of expression of the Cl importer NKCC1 and Cl exporter KCC2- has been implicated in several neurodevelopmental disorders (e.g., Down syndrome, DS). Interestingly, NKCC1 inhibition by the FDAapproved diuretic bumetanide reverts cognitive deficits in the TS65Dn mouse models of DS and core symptoms in a number of models of other brain disorders. However, the required chronic treatment with bumetanide is burdened by its diuretic side effects caused by the antagonism of the kidney Cl- importer
NKCC2, which leads to hypokalemia and jeopardizes drug compliance. Crucially, these issues would be solved by selective NKCC1 inhibitors, thus devoid of the diuretic effect. Starting from bumetanide’s structure, we applied a computational ligand-based approach to design new molecular entities that we tested in vitro for their capacity to selectively block NKCC1. Among the 3 newly-identified and highly promising NKCC1 inhibitors, one showed excellent solubility and metabolic stability in vitro. Moreover, analysis of WT and Ts65Dn mice systemically treated with this NKCC1 inhibitor revealed no diuretic effect. Finally, chronic treatment with our novel, selective NKCC1 inhibitor was able to rescue cognitive deficits in Ts65Dn mice in four different memory tasks, with no major signs of toxicity. Thus, our selective NKCC1 inhibitor devoid of the diuretic effect could represent a suitable and solid therapeutic strategy for the treatment of Down syndrome and all the brain disorders with depolarizing GABAergic transmission.
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Zhang, Chuanqiang [Verfasser], Knut [Gutachter] Kirmse, Otto W. [Gutachter] Witte et Valentin [Gutachter] Stein. « Role of depolarizing GABAergic transmission for cortical network development / Chuanqiang Zhang ; Gutachter : Knut Kirmse, Otto W. Witte, Valentin Stein ». Jena : Friedrich-Schiller-Universität Jena, 2019. http://d-nb.info/1206605057/34.
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Heise, C. « EUKARYOTIC ELONGATION FACTOR 2 KINASE DOWNREGULATES VESICLE RELEASE AND GABAERGIC TRANSMISSION BY TRANSLATION CONTROL OF A SUBSET OF PROTEINS ». Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229422.
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eEF2K, also known as CAMKIII, is a highly regulated, ubiquitous kinase involved in the control of protein translation. In neurons, acute changes in eEF2K activity are associated with changes in synaptic proteome and function in vitro and in vivo. However, it is unclear what kind of synaptic proteomic and functional changes result from chronic alterations in eEF2K activity. Here we show that chronic eEF2K activity leads to a downregulation of vesicle release and the GABAergic system both in vitro and in vivo. Importantly, we show that eEF2K may be a potential target for the generation of antiepileptic drugs.
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Spehl, Marco Simon [Verfasser], et Bela [Akademischer Betreuer] Szabo. « Analyse der Wirkung von CB1-Cannabinoidrezeptor-Antagonisten auf die GABAerge synaptische Transmission im Cerebellumcortex ». Freiburg : Universität, 2013. http://d-nb.info/1123480192/34.
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Heubl, Martin. « Régulation rapide du co-transporteur neuronal K/Cl KCC2 par l'inhibition et l'excitation dans les neurones matures ». Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066073.
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La polarité et l'efficacité de la transmission GABAergique dépendent de la concentration intra-neuronale en chlore. Dans les neurones matures, le co-transporteur K+/Cl- KCC2 maintient la concentration intracellulaire en chlore à un niveau bas, permettant ainsi une réponse inhibitrice du GABA. En plus de son rôle dans la transmission GABAergique, KCC2 régule aussi l'efficacité de la transmission glutamatergique en contrôlant la spinogenèse, l'exocytose et la dynamique membranaire des récepteurs AMPA. Du fait de son importance aux synapses excitatrices et inhibitrices, il est crucial de comprendre les mécanismes qui régulent l'expression membranaire et la fonction de KCC2. La régulation de KCC2 par l'activité glutamatergique excitatrice ayant été bien caractérisée, il reste à déterminer si l'expression et la fonction de KCC2 sont régulées par l'activité inhibitrice GABAergique. Pendant ma thèse, j'ai montré que KCC2 est en effet directement régulé par la transmission GABAergique. J'ai trouvé que l'activation aigue des RGABAA confine KCC2 dans la membrane alors que le blocage des RGABAA augmente la dynamique membranaire et l'internalisation du transporteur. Les mécanismes moléculaires impliquent le chlore comme messager secondaire, la kinase WNK1 et la phosphorylation de KCC2 sur des résidus thréonines clés. J'ai ensuite pu montrer que cette régulation à un impact aux synapses inhibitrice et excitatrice. Mon travail propose un mécanisme nouveau de la régulation de l'homéostasie du chlore par l'inhibition GABAergique. Ainsi les neurones peuvent compenser une augmentation ou une diminution en chlore neuronale par une adaptation rapide de KCC2 à la surface cellulaireThe polarity and efficacy of GABAergic neurotransmission depends on the intraneuronal chloride concentration. In mature neurons chloride extrusion by the K+/Cl- co-transporter KCC2 permits an inhibitory influx upon activation of GABAA receptors. In addition to its role in GABAergic transmission, KCC2 regulates also glutamatergic transmission in an ion-independent manner by controlling spinogenesis and AMPAR exocytosis and membrane diffusion in dendritic spines. Knowing its pivotal role at central synapses, it is of particular importance to understand the cellular and molecular mechanisms underlying its regulation. While regulation of KCC2 by neuronal excitation is well documented, it is still unknown whether neuronal inhibition itself can regulate the transporter’s membrane expression and/or activity. During my PhD I was able to demonstrate a direct regulation of KCC2 membrane diffusion and stability by GABAA receptor-mediated inhibition and I characterized the underlying signaling cascade. I found that activation of GABAAR decreased KCC2 lateral diffusion while GABAAR blockade led to increased membrane dynamics and internalization of the transporter. I could show that KCC2 regulation by neuronal inhibition requires chloride as second intracellular messenger and chloride-sensing WNK1 kinase that directly phosphorylate KCC2 on key Threonine residues. This regulation has a functional impact at both excitatory and inhibitory synapses. My work reports a novel and rapid mechanism of control of chloride homeostasis by GABAA receptor-mediated inhibition that allows maintaining the polarity and activity of GABAA receptors constant
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Kourdougli, Nazim. « Hippocampal structural reactive plasticity in a rat model of temporal lobe epilepsy : chloride homeostasis as a keystone ». Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM4091.
Texte intégralRésumé :
Cette thèse a pour objectif spécifique d’explorer les événements précoces pouvant être à l’origine du bourgeonnement aberrant des fibres moussues (FM) du gyrus denté, une réorganisation majeure dans l’Epilepsie du Lobe Tempora (ELT). Nous avons utilisé le modèle pilocarpine d’ELT chez le rat afin de montrer que la transmission GABAergique jouait un rôle prépondérant dans la formation des FM aberrantes au cours de l’épileptogenèse. Ceci étant due à une altération de l’homéostasie chlore, suite à une augmentation de l’expression du co-transporteur NKCC1 et une diminution du co-transporteur KCC2. Nos résultats ont démontré que le récepteur aux neurotrophines p75NTR était un médiateur de l’action trophique de la réponse GABAergique dépolarisante sur le bourgeonnement aberrant des FM. Le blocage de l’action dépolarisante de la transmission GABAergique via l’utilisation de la bumétanide, a permis de réduire le bourgeonnement aberrant des MF en réduisant l’expression de p75NTR. Enfin, l’application transitoire de la bumétanide au cours de l’épileptogenèse a abouti à la réduction du nombre de crises récurrentes et spontanées au cours de la phase chronique d’ELT chez le rat. Ce travail a permis de dévoiler les mécanismes moléculaires sous-jacents de la réorganisation du réseau neuronal glutamatergique consécutif à une crise inaugurale dans un modèle d’ELT. Dans l'ensemble, cette thèse apporte un éclairage nouveau sur l’importance de l’interaction de la signalisation GABAergique avec les neurotrophines afin d’orchestrer la plasticité réactive au sein de l’hippocampe dans TLEThe present dissertation undertakes to investigate the early triggering events of the mossy fiber sprouting (MFS) in the dentate gyrus, a hallmark of hippocampal reactive plasticity in Temporal Lobe Epilepsy (TLE). We used the rat pilocarpine model of TLE to show that altered GABAA receptor-mediated transmission play a key role in the formation of early ectopic MFS during epileptogenesis. This is likely due to a compromised chloride homeostasis, as a result of increased expression of chloride loader NKCC1 and downregulation of the neuronal chloride extruder KCC2. We next addressed the mechanistic action of depolarizing GABAAR responses with regard to neurotrophin signaling. Our findings uncovered that the pan neurotrophin receptor p75 (p75NTR) mediated the sculpting action of depolarizing GABAAR responses on the ectopic MFS. Blockade of depolarizing GABAAR responses using the loop diuretic bumetanide reduced abnormal p75NTR subsequently decreased the ectopic MFS. Finally, transitory application of bumetanide during epileptogenesis resulted in reduction of spontaneous and recurrent seizures during the chronic phase of TLE. The rationale of this work is that unveiling the molecular mechanisms underlying the hippocampal post-seizure glutamatergic network rewiring will help to drive future novel therapeutic avenues involving chloride homeostasis and neurotrophin interplay. Overall, this dissertation shed a new light on how GABAergic transmission and neurotrophin signaling crosstalk can orchestrate reactive hippocampal plasticity in TLE
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Dik, Andre [Verfasser], et Weiqi [Akademischer Betreuer] Zhang. « Hemisphärenspezifische Wirkung von Erythropoetin auf die GABAerge Transmission in dem prälimbischen Cortex / Andre Dik ; Betreuer : Weiqi Zhang ». Münster : Universitäts- und Landesbibliothek Münster, 2016. http://d-nb.info/1140169114/34.
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Werner, Christian [Verfasser], Claudia [Gutachter] Sommer, Marie-Christine [Gutachter] Dabauvalle et Erhard [Gutachter] Wischmeyer. « Effect of autoantibodies targeting amphiphysin or glutamate decarboxylase 65 on synaptic transmission of GABAergic neurons / Christian Werner. Gutachter : Claudia Sommer ; Marie-Christine Dabauvalle ; Erhard Wischmeyer ». Würzburg : Universität Würzburg, 2014. http://d-nb.info/1108780873/34.
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BOLLA, MARIA. « "Investigation on the role of Cl- homeostasis and GABAergic transmission in sleep disorders of Down syndrome and in Prader Willi syndrome : a possible contributor to cognitive impairment" ». Doctoral thesis, Università degli studi di Genova, 2020. http://hdl.handle.net/11567/996395.
Texte intégralRésumé :
GABA is the main inhibitory neurotransmitter of the central nervous system (CNS). Recently,
GABAergic transmission has been reported to be depolarizing and possibly excitatory rather than
inhibitory in a number of neurodevelopmental disorders both in patients and mouse models.
In particular, the Ts65Dn mouse model of Down syndrome (DS) exhibits depolarizing GABA due to
upregulation of the Cl- importer NKCC1 both in the hippocampus and in the cortex. Moreover,
NKCC1 inhibition by the FDA-approved diuretic bumetanide is able to rescue inhibitory GABAergic
transmission, synaptic plasticity and cognitive functions in Ts65Dn mice.
Beside cognitive impairment, DS mice and people with DS show sleep disturbaces. Since sleep
pattern is regulated by GABAergc transmission, we reasoned that the alteration of GABAergic
transmission due to upregulation of NKCC1 might be underlying at least some of the sleep
disturbances in DS mice. So, we characterized sleep in Ts65Dn mice and investigated the effects of
a chronic treatment with bumetanide. We found that bumetanide ameliorates the quality of sleep
in NREM and REM sleep phases before and after sleep deprivation and decreases abnormal
wakefulness during light phase at baseline in Ts65Dn mice. Moreover, we also found abnormalities
in other parameters, which could contribute to sleep abnormalities of Ts65Dn mice: an increase of
food intake and activity (partially rescued by bumetanide) with a reduction of body temperature
during dark phase.
Because of the association of altered GABAergic signaling by dysregulation of the expression of
NKCC1 (but also of the Cl- exporter KCC2) in many neurodevelopmental disorders characterized by
cognitive or social impairment, and sleep disorders, we extended our studies to Prader Willi
syndrome (PWS). PWS is a neurodevelopmental disorder, caused by defects of genomic imprinting
and characterized by cognitive, social and sleep abnormalities. Here, we observed that the Snord116
5
mutant mouse model of PWS, PWScrm+/p− show an increased expression of NKCC1, specifically in the
hippocampus in comparison to their wild-type mice. Moreover, we report that PWS mice have
altered cognition and the circadian period in free-running conditions. In particular, mutant mice
present defects of long-term memory and a reduced shortening of their circadian period together
with an increase of alpha activity in dark-dark (DD). Moreover, they also show alteration of pain
sensitivity, that could be linked to defects in the thermoregulation. Interestingly, in constrast with
PWS people, Snord116 mutant mice showed no alterations of anxiety, repetivive, obsessive and
social behaviors.
In an effort to rescue cognition and the circadian phenotype by rescuing NKCC1 inhibition, we
treated Snord116 mutant mice with bumetanide. Remarkably, bumetanide treatment resulted in a
complete rescue of the cognitive defects and circadian alteration in DD, with no effects in controls.
Our results suggest an important link between GABA transmission and the regulation of cognition
and the circadian clock in PWS. In addition, the current study extends the repertoire of disorders in
which NKCC1 inhibition attenuates behavioural deficits and proposes a new potential mechanism
for the investigation of PWS.
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Linder, Sophia [Verfasser], et Bela [Akademischer Betreuer] Szabo. « Klärung des Wirkmechanismus des Cannabinoid-Rezeptor-Antagonisten Rimonabant auf die GABAerge synaptische Transmission zwischen Interneuronen und Purkinjezellen im Cerebellum / Sophia Linder ; Betreuer : Bela Szabo ». Freiburg : Albert-Ludwigs-Universität Freiburg, 2017. http://d-nb.info/112692086X/34.
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Höfelmann, Daniela [Verfasser], Gerhard K. [Akademischer Betreuer] Rammes et Harald [Akademischer Betreuer] Luksch. « Mögliche Interaktionen des endocannabinoiden Systems mit dem 5-HT3-Rezeptor in der Amygdala : Untersuchungen zur Bedeutung für die Modulation der GABAergen synaptischen Transmission und Furchtkonditionierung / Daniela Höfelmann. Gutachter : Harald Luksch. Betreuer : Gerhard K. Rammes ». München : Universitätsbibliothek der TU München, 2012. http://d-nb.info/1025337719/34.
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Donato, Cristina. « Synaptic identity of neocortical circuits involving Martinotti cells in healthy conditions and in Down syndrome ». Thesis, Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=http://theses-intra.upmc.fr/modules/resources/download/theses/2019SORUS079.pdf.
Texte intégralRésumé :
Les interneurones GABAergiques du néocortex, englobent un grand nombre de types cellulaires: certains innervent la région périsomatique des neurones pyramidaux (NP), d'autres ciblent leurs dendrites. Ici, nous avons étudié la sous-unité alpha5 du récepteur GABAA(GABAAR), qui contribuerait significativement à l’inhibition tonique. Nous avons constaté que, dans les NP de la couche 2/3 du cortex somatosensoriel chez la souris, alpha5 a une contribution négligeable à l'inhibition tonique. Inversement nous avons montré qu’alpha5 est spécifiquement exprimée aux synapses dendritiques entre les cellules de Martinotti (MC) et les NP, indiquant l’importance des alpha5-GABAARs dans l’inhibition dendritique synaptique. Nous avons aussi montré qu’alpha5 est exclusivement exprimé aux synapses MC-NP, en proposant les alpha5-GABAARs comme signature moléculaire spécifique de ces synapses dendritiques. En plus, des nombreuses maladies du cerveau sont le résultat du dysfonctionnement de circuits inhibiteurs distincts: par exemple, il a été montré que le traitement avec un agoniste inverse spécifique du récepteur alpha5-GABAA(alpha5IA) a permis la récupération des déficits cognitifs chez des modèles animaux de trisomie 21(DS) mais les mécanismes de cette récupération cognitive sont inconnus au niveau du circuit. Nos résultats préliminaires indiquent que les synapses GABAergiques dendritiques formées par les MCs sont spécifiquement modifiées chez les souris DS. Nous définirons si cette modification est spécifique à un circuit particulier. Nos expériences visent à comprendre les altérations spécifiques des circuits de la DS afin d’ouvrir de nouvelles pistes thérapeutiquesNeocortical GABAergic interneurons encompass a vast number of cell types: some innervate the perisomatic region of cortical pyramidal neurons (PNs), whereas others target PN dendrites. Here we studied the alpha5 subunit of the GABAAR, which is believed to contribute significantly to tonic inhibition. We found that, in L 2/3 PNs of mouse somatosensory cortex, alpha5 provides a negligible contribution to tonic inhibition. Conversely, we found that alpha5 is specifically expressed at synapses between the dendrite-targeting interneurons Martinotti cells (MCs) thus indicating that GABAergic transmission through 5-GABAAR subtypes is important for synaptic dendritic inhibition. We also show that the expression of alpha5 is always present only at synapses made by MCs onto PNs. These results suggest alpha5-GABAARs as a molecular signature of specific inhibitory dendritic synapses involving MCs. Importantly, many brain diseases originate from dysfunctions of distinct inhibitory circuits and, in particular, alpha5-KO mice show improved learning: it was shown that the treatment with a highly specific alpha5 inverse agonist rescued learning and memory deficits in Ts65Dn mice, an animal model for Down syndrome (DS). Yet, the actual mechanisms underlying this cognitive rescue at the synaptic and circuit levels are unknown. Our preliminary results indicate that GABAergic synapses from dendrite-targeting MCs are specifically altered in DS. We are defining whether this alteration is circuit-specific. Our results will provide a better understanding of specific circuit alterations in DS, and will likely open new therapeutic avenues to alleviate cognitive impairment of this disease
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Zell, Vivien. « Impact des glucocorticoïdes circulants sur la maturation et le fonctionnement de l'inhibition spinale GABAergique ». Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ097/document.
Texte intégralRésumé :
Les glucocorticoïdes (GC) sont des hormones stéroïdes synthétisées par les glandes surrénales. La production de ces GC est une des réponses de l’organisme pour rétablir l’homéostasie grâce à différentes actions comprenant des effets centraux sur le comportement et la douleur. C’est ce dernier qui a fait l’objet de mes travaux dans le cadre de cette thèse.Les afférences sensorielles primaires véhiculent les informations de la périphérie dans les cornes dorsales de la moelle épinière. Ces informations qui peuvent être nociceptives sont modulées par un réseau de neurones spinal avant d’être transmises et intégrées. Nous avons montré que les GC sont impliqués dans la maturation et le fonctionnement de la transmission inhibitrice faisant intervenir le neurotransmetteur GABA. Dans les cornes dorsales, cette inhibition est cruciale pour limiter les mécanismes de transmission de l’information nociceptiveGlucocorticoids (GC) are steroid hormones synthesized in adrenals following HPA axis activation. GC production is a response of the organism to alleviate homeostasis perturbations through different actions. One of them involves central neuronal modulation of behavior and pain perception.Primary afferents convey peripheral sensory information in the dorsal horns of the spinal cord. This information can be nociceptive and are modulated by a spinal neuronal network before being transmitted and integrated. We showed that GC are implied in the maturation and functioning of the inhibitory transmission involving GABA neurotransmitter. In the dorsal horns this inhibitory transmission is of major importance, limiting the processing of nociceptive information
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Özcan, Orçun Orkan. « Characterization of the Purkinje cell to nuclear cell connections in mice cerebellum ». Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ085/document.
Texte intégralRésumé :
Le cervelet permet l’apprentissage moteur et la coordination des mouvements fins. Pour ce faire, il intègre les informations sensorielles provenant de l’ensemble du corps ainsi que les commandes motrices émises par d’autres structures du système nerveux central. Les noyaux cérébelleux profonds (DCN) constituent la sortie du cervelet et intègre les informations provenant des cellules de Purkinje (PC), des fibres moussues et des fibres grimpantes. Nous avons étudié les connexions fonctionnelles entres les PC et les DNC in vivo, grâce à une stimulation optogénétique des lobules IV/V du cortex cérébelleux et à l’enregistrement multi unitaire du noyau médian. Nous avons ainsi identifié deux groupes de cellules au sein des DCN, présentant des caractéristiques propres au niveau de leur fréquence de décharge et de la forme des potentiels d’action, en accord avec la dichotomie établie par une précédente étude in vitro permettant de séparer les neurones GABAergiques des autres neurones. Nos résultats suggèrent que les PC contrôlent la sotie du cervelet d’un point de vue temporel. De plus, la ciruiterie interne des DCN conforte ce résultat de part le fait que les cellules GABAergiques ne produisent pas d’effet temporel au travers de l’inhibition localeThe cerebellum integrates motor commands with somatosensory, vestibular, visual and auditory information for motor learning and coordination functions. The deep cerebellar nuclei (DCN) generates the final output by processing inputs from Purkinje cells (PC), mossy and climbing fibers. We investigated the properties of PC connections to DCN cells using optogenetic stimulation in L7-ChR2 mice with in vivo multi electrode extracellular recordings in lobule IV/V of the cerebellar cortex and in the medial nuclei. DCN cells discharged phase locked to local field potentials in the beta, gamma and high frequency bands. We identified two groups of DCN cells with significant differences in action potential waveforms and firing rates, matching previously discriminated in vitro properties of GABAergic and non-GABAergic cells. PCs inhibited the two group of cells gradually (rate coding), however spike times were controlled for only non-GABAergic cells. Our results suggest that PC inputs temporally control the output of cerebellum and the internal DCN circuitry supports this phenomenon since GABAergic cells do not induce a temporal effect through local inhibition
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Orcinha, Catarina Reis. « GABAergic transmission impairment promotes the glycinergic phenotype ». Master's thesis, 2012. http://hdl.handle.net/10451/9222.
Texte intégralRésumé :
Tese de mestrado em Bioquímica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2012A transmissão inibitória desempenha um papel importante na regulação e estabilização da actividade neuronal e é essencial para diversas funções cerebrais como a cognição, percepção, movimento e emoção. As sinapses inibitórias, GABAérgica e glicinérgica, e a sua distribuição, apresentam diferenças no sistema nervoso central dos mamíferos (CNS). A maioria das sinapses inibitórias no cérebro são GABAérgicas, e as glicinérgicas, predominantes na espinal medula e tronco cerebral, tem sido bastante negligenciadas no cérebro. A glicina exerce a sua função através do receptor ionotrópico da glicina (GlyR), um canal pentamérico composto por dois tipos de subunidades (α e β) permeável a iões cloreto e localizado na membrana do terminal pós-sináptico. Os transportadores da glicina 2 (GlyT2) pertencem à família de transportadores dependentes de Na+/Cl-. Estão presentes na membrana dos terminais pré-sinápticos glicinérgicos, assegurando a remoção da glicina da fenda sináptica e permitindo a inserção do neurotransmissor em vesículas sinápticas. O presente estudo tem como principal objectivo investigar quais os principais intervenientes na aquisição do fenótipo glicinérgico. Para isso, efectuou-se uma abordagem farmacológica, em culturas primárias de neurónios, com o propósito de avaliar o fenótipo glicinérgico mediante o comprometimento da transmissão GABAérgica. Os resultados obtidos por western blot e por PCR quantitativo (qPCR) revelaram que a expressão de GlyR e de GlyT2 aumentava significativamente, após tratamento das células com antagonistas do receptor ionotrópico de GABA GABAA (GABAAR) ou do transportador de GABA GAT-1, gabazina e SKF89976a, respectivamente. Em sinaptossomas obtidos de cérebro, a dupla detecção por imunofluorescência, de GlyT2 (marcador de neurónios glicinérgicos) e GAD (marcador de neurónios GABAérgicos) revelou igualmente que, na presença de SKF89976a, a razão entre terminais GABAérgicos e glicinérgicos se apresentava alterada. O comprometimento do sistema GABAérgico resultou no aumento de terminais glicinérgicos puros e mistos, com a consequente diminuição de terminais GABAérgicos. Neste trabalho, a interacção entre o transportador vesicular de aminoácidos inibitórios (VIAAT) e o GlyT2 foi igualmente explorada por ensaios de imunoprecipitação. Os resultados obtidos nesta tese evidenciam, pela primeira vez, que o comprometimento da neurotransmissão GABAérgica induz um aumento dos marcadores da transmissão mediada pela glicina, nomeadamente GlyR e GlyT2, sugerindo assim um mecanismo de compensação entre os dois sistemas inibitórios no cérebro.
The inhibitory transmission plays an important role in the regulation and stabilization of brain network activity and is essential for a number of brain functions such as cognition, perception, movement and emotion. GABAergic and glycinergic inhibitory synapses, and their distribution, are very different in the mammalian central nervous system (CNS). Most inhibitory synapses in the brain are GABAergic, and glycinergic ones, predominant in the most caudal regions of the CNS, have been largely disregarded in the brain. Glycine exerts its action through glycine receptors (GlyR), which belong to the superfamily of ligand-gated ion channels, are localized in the postsynaptic membrane and form pentameric channels composed of two different subunits (α and β) permeable to chloride ions. Glycine transporters 2 (GlyT2) belong to the family of Na+/Cl--dependent transporter proteins. They are located in the membrane of glycinergic neurons and are responsible for terminating glycine-mediated neurotransmission by uptaking glycine into glycinergic nerve terminals, allowing for neurotransmitter reloading of synaptic vesicles. The present study aims to investigate which are the principal mediators for the acquisition of a glycinergic phenotype. A pharmacological approach, in primary neuronal cultures, was pursued in order to evaluate the glycinergic phenotype upon a GABAergic transmission impairment. Western blot analysis and quantitative real-time PCR (qPCR) revealed that GlyR and GlyT2 expression increased significantly after treating the cultures with blockers for either GABAA receptor or GABA transporter GAT-1, gabazine and SKF89976a, respectively. In brain synaptosomes, double immunofluorescence of GlyT2 (marker of glycinergic neurons) and GAD (marker of GABAergic neurons) also revealed that, in the presence of SKF89976a, the ratio of GABAergic vs glycinergic terminals changed. GABAergic impairment caused an increase in mixed (GABA and glycine-containing) and pure glycinergic terminals, with a concomitant decrease in GABA-containing boutons. Furthermore, a physical interaction was assessed between Vesicular Inhibitory Amino Acid Transporter (VIAAT) and GlyT2 by immunoprecipitation assays. These results obtained in this thesis have elucidated, for the first time, that impairment in GABA-mediated neurotransmission induces an increase in glycine- mediated transmission components, namely GlyR and GlyT2, and suggest a compensatory mechanism between the two inhibitory systems in the brain.
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Huang, Yu-Yin, et 黃昱尹. « The Lamotrigine-Mediated Effect on Hippocampal GABAergic Transmission ». Thesis, 2016. http://ndltd.ncl.edu.tw/handle/44w2jv.
Texte intégralRésumé :
博士國立陽明大學
臨床醫學研究所
105
Lamotrigine (LTG) is generally considered as a voltage-gated sodium (Nav) channel blocker, which can decrease neuronal excitability. However, recent studies suggest that LTG can also serve as a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel enhancer and can increase the excitability of GABAergic interneurons (INs). Perisomatic inhibitory INs, predominantly fast-spiking basket cells (BCs), powerfully inhibit granule cells (GCs) in the hippocampal dentate gyrus. Notably, BCs express abundant Nav channels and HCN channels, both of which are able to support sustained action potential generation. Using patch-clamp whole-cell recording in acute rat hippocampal slices, we investigated the net LTG effect on BC excitability and its GABAergic output. We showed that bath application of LTG significantly decreased the amplitude of evoked compound inhibitory postsynaptic currents (IPSCs) in GCs. In contrast, simultaneous paired recordings from BCs to GCs showed that LTG had no effect on both the amplitude and the multiple-pulse ratio of the unitary IPSCs, suggesting that LTG did not affect GABA release probability at BC axonal terminal, though it suppressed cell excitability. In line with this, LTG decreased spontaneous IPSC (sIPSC) frequency, but not miniature IPSC frequency. When re-examining the LTG effect on GABAergic transmission in the cornus ammonis region 1 (CA1) area, we found that LTG markedly inhibited both the excitability of dendrite-targeting INs in the stratum oriens and the concurrent sIPSCs recorded on their targeting pyramidal cells (PCs) without significant hyperpolarization-activated current (Ih) enhancement. In summary, LTG has no effect on augmenting Ih in GABAergic INs and does not promote GABAergic inhibitory output. The antiepileptic effect of LTG is likely through Nav channel inhibition and the suppression of global neuronal network activity.
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Rombo, Diogo Miguel Santos 1986. « Modulatory role of adenosine upon GABAergic transmission : consequences for excitability control ». Doctoral thesis, 2015. http://hdl.handle.net/10451/22913.
Texte intégralRésumé :
Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2015Glutamatergic principal cell excitability in the hippocampus is regulated by local circuit neurons that release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). These GABAergic interneurons exhibit vast structural, physiological and biochemical diversity, innervating both excitatory principal cells and other inhibitory interneurons. In the hippocampus, two classes of interneurons, the cholecystokinin (CCK)- and parvalbumin (PV)-containing neurons, are the most significant and abundant cell type displaying unique and complementary functions in the control of principal cells output. Hence a tuned modulation of inhibitory circuits is of great importance in the control of network hippocampal function. Adenosine, acting through high affinity A1 receptor (A1R) and A2A receptor (A2AR), is a well-recognized endogenous modulator of glutamatergic principal cells excitability. Actions mediated by A1Rs are long-known to decrease hippocampal excitability with neuroprotective effects while actions through A2ARs are associated with increased neuronal excitability and excitotoxicity. However, the role of adenosine to modulate inhibitory transmission is much less known. This work aimed to evaluate and characterize the involvement of A1Rs (Chapter 5.1, p99) and A2ARs (Chapter 5.2, p143) on inhibitory neuronal communication in CA1 hippocampus and its impact on principal cells excitability and in the control of epileptiform discharges. These main goals were achieved by performing ex vivo electrophysiology recordings (field and patch-clamp recordings) from rat and mice hippocampus. Regarding A1R-actions, it was found that tonic - mediated by GABA receptor type A (GABAAR) localized peri- and extrasynaptically - but not phasic - mediated by GABAARs located at synapses - inhibitory transmission in pyramidal cells and CCKpositive interneurons were diminished after A1R activation. The effect was dependent on a signaling cascade involving both protein kinase A (PKA) and protein kinase C (PKC) and was accompanied by decreased GABAAR δ-subunit expression. On the other hand, it was also found that A2AR-mediated increase in pyramidal cells excitability results from a direct increase of glutamatergic transmission in parallel with disinhibition of principal cells by a mechanism that involves increased GABA release from PV-positive cells to other interneurons. Also, A2AR activation or blockage respectively promotes or reduces synchronous pyramidal cell firing in hyperexcitable conditions induced by elevated extracellular potassium or following high-frequency electrical stimulation. Together the results presented in this thesis show for the first time a direct involvement of adenosine receptors in the control of inhibitory network transmission in the hippocampus. This results open new promising perspectives for the involvement of adenosine in the control of physiological hippocampal operations and maladaptive conditions.
A transmissão glutamatérgica no hipocampo é continuamente controlada por neurónios inibitórios, denominados interneurónios, que libertam o neurotransmissor ácido gama-aminobutírico (GABA). Estas células apresentam uma grande diversidade anatómica, fisiológica e bioquímica, estando descritos mais de vinte e um tipos diferentes de interneurónios no hipocampo. Estes são capazes de comunicar quer com células principais excitatórias (denominadas células piramidais), quer com outros interneurónios inibitórios, com resultados diferentes para a excitabilidade do sistema. A inibição de células piramidais leva a uma diminuição direta da sua excitabilidade; ao passo que a inibição de outros interneurónios pode resultar na desinibição das células principais e consequente aumento da excitabilidade. Desta grande variedade de interneurónios, destacam-se duas grandes classes que correspondem às duas populações de interneurónios mais importantes e abundantes no hipocampo – os neurónios que expressam colecistocinina (CCK) e os neurónios que expressam parvalbumina (PV). As funções de cada uma destas populações no hipocampo são únicas e complementares no controlo da atividade das redes neuronais. Desta forma, um controlo rigoroso destes circuitos inibitórios é de extrema importância na regulação das funções do hipocampo. A adenosina é um neuromodulador ubíquo do sistema nervoso central que atua através de dois grandes tipos de recetores de alta afinidade – os recetores A1 (A1R) e os recetores A2A (A2AR). Os primeiros têm ações principalmente inibitórias da excitabilidade neuronal, e portanto estão normalmente associados a funções neuroprotetoras, enquanto os segundos atuam no sentido de aumentar a excitabilidade no hipocampo e induzir excitotoxicidade. Enquanto que a função da adenosina no controlo da transmissão excitatória glutamatérgica tem vindo a ser caracterizada há várias décadas, o papel da adenosina na modulação da transmissão inibitória tem sido muito menos explorada. O trabalho apresentado nesta tese tem como objetivo a caracterização das ações dos A1Rs (Capítulo 5.1, p99) e dos A2ARs (Capítulo 5.2, p143) na comunicação neuronal inibitória no hipocampo bem como tentar perceber quais as consequências que uma possível modulação a este nível tem na excitabilidade das células piramidais e no desenvolvimento de atividade do tipo epiléptica. Para responder a estas questões foi planeado e executado um trabalho experimental que envolveu o registo da atividade elétrica neuronal no hipocampo de ratos e ratinhos através de técnicas eletrofisiológicas ex vivo (nomeadamente registos extracelulares e registos de patch-clamp). Relativamente às ações dos A1Rs, foi demonstrado que apenas um tipo de respostas inibitórias, denominadas por respostas tónicas, são afetadas pela ativação dos A1Rs, levando à sua diminuição. Este tipo de resposta tónica tem caraterísticas lentas e prolongadas no tempo e é mediada principalmente por recetores ionotrópicos do GABA do tipo A (GABAAR) que estão localizados em porções peri- e extrasináticas dos neurónios. Pelo contrário, as respostas habitualmente rápidas e concertadas no tempo, denominadas por respostas fásicas, e que são mediadas por recetores localizados nas sinapses, não parecem ser afetadas pela ativação dos A1Rs. Curiosamente, estas ações ocorrem seletivamente em neurónios excitatórios piramidais e numa subpopulação de interneurónios que expressam o neuropéptido CCK. O efeito dos A1Rs na diminuição das respostas tónicas está associado a uma cascata de sinalização intracelular que envolve as proteínas cinase A (PKA) e C (PKC) e é acompanhado pela diminuição da expressão de GABAARs que contêm a subunidade δ, habitualmente implicada nas respostas tónicas. Neste trabalho foi também demonstrado que a adenosina, através dos A2ARs, também influencia a transmissão inibitória no hipocampo. De facto, os efeitos da ativação dos A2ARs levam a um aumento da excitabilidade das células piramidais, que pode ser explicado pela ação destes recetores em dois locais: (1) a ativação dos A2ARs aumentam diretamente as respostas glutamatérgicas sobre as células piramidais; (2) simultaneamente, os A2ARs vão desinibir as células principais através de um mecanismo que envolve o aumento da libertação de GABA dos terminais sinápticos de neurónios que expressam PV e que contactam com outros neurónios inibitórios. Estas ações moduladoras têm implicações importantes em modelos de hiperexcitabilidade neuronal induzida pelo aumento das concentrações extracelulares de potássio, na medida em que a ativação ou inibição dos A2ARs leva a um exacerbação ou diminuição, respetivamente, desta hiperatividade neuronal sincronizada. No seu conjunto, os resultados apresentados nesta tese revelam, pela primeira vez, o envolvimento dos recetores de adenosina na modulação da transmissão neuronal inibitória no hipocampo. Estes resultados poderão abrir novas e promissoras perspetivas relativamente ao envolvimento da adenosina no controlo das funções do hipocampo em condições fisiológicas e patológicas.
Network of European Neuroscience Schools; Medical Research Council
34
Morishita, Wade Katsuji. « Studies on GABAergic synaptic transmission in neurons of the deep cerebellar nuclei ». Thesis, 1995. http://hdl.handle.net/2429/4783.
Texte intégralRésumé :
In the cerebellum, the corticonuclear projection subserves as the major efferent
pathway for the cerebellar cortical networks. This pathway, consists of a direct axonal
projection from the Purkinje cells to the neurons of the deep cerebellar nuclei (DCN). It
has been demonstrated both in vivo and in vitro that stimulation of the Purkinje cell
axons exerts a powerful inhibitory influence on DCN neurons mediated by the
neurotransmitter, ƴ-aminobutyric acid (GABA). However, despite the wealth of
anatomical and biochemical information, few electrophysiological studies have been
done to characterize GABAergic synaptic transmission in DCN neurons. For example,
it is not clear whether synaptic release of GABA activates pre- or postsynaptic GABAB
receptors despite the finding that GABAB binding sites are present in the DCN.
Furthermore, although GABAergic transmission in the DCN exhibits paired-pulse,
frequency-dependent, as well as long-term depressions, the mechanisms underlying
these plasticity's are yet to be resolved. In the present study, both perforated and
whole-cell patch clamp recording techniques were utilized to determine whether preand
postsynaptic GABAB receptors are present in the DCN and to test if endogenous
release of GABA can activate either of the receptors. In addition, the contribution of
GABAB receptors to paired-pulse and frequency-dependent depression of the deep
nuclear inhibitory postsynaptic current (IPSC) was also assessed. Finally, experiments
were conducted to investigate the properties of a tetanic stimulation-induced deep
nuclear long-term depression (LTD) of the IPSC and to examine the role of Ca^2+ and
protein phosphatases as potential mediators of the sustained depression. The results of the studies indicated that postsynaptic GABAB receptors are
present on the membrane of DCN neurons. Activation of these receptors produces a
G-protein-dependent response similar to that observed in other central neurons. In
addition, presynaptic GABAB receptors are also present in the DCN. Activation of these
receptors produces a suppression of deep nuclear IPSCs. However, deep nuclear preand
postsynaptic GABAB receptors were found not to be activated by endogenous
release of GABA. Furthermore, these receptors appear not to be involved in pairedpulse
and frequency-dependent depressions of the IPSC.
In voltage-clamped DCN neurons, LTD of the IPSC was induced reliably if the
LTD-inducing train was delivered under current-clamp conditions where the membrane
potential was allowed to fluctuate. Using this protocol in subsequent experiments, it
was found that currents elicited by iontophoretic applications of THIP, a GABAA agonist,
also exhibited LTD following a tetanic stimulation of the input. It was also demonstrated
that LTD can be induced heterosynaptically. Furthermore, activation of the IPSC during
the train was not required for LTD to occur. However, postsynaptic Ca^2+ accumulations
via influx though A/-methyl-D-aspartate receptor-gated channels and/or voltage-gated
Ca^2+ channels appear to play an important role in the generation of LTD. Moreover,
protein phosphatase activity appears to be necessary for the induction of the
depression. It is concluded that postsynaptic mechanisms contribute to LTD of
GABAergic transmission in neurons of the DCN.
Bhagavatula R. Sastry, Ph.D.,
Research Supervisor.
35
Le, Gratiet Keyrian Louis. « Differential distribution of co-transmitted cholinergic and GABAergic synaptic inputs onto substantia nigra dopaminergic neurons ». Thesis, 2021. http://hdl.handle.net/1828/12887.
Texte intégralRésumé :
Neuronal communication in the mammalian brain relies on the presynaptic release of neurotransmitters which bind to ligand-gated ion channels found on postsynaptic neurons to modulate neuronal excitability. One such neurotransmitter is acetylcholine (ACh), a small molecule that is the signalling messenger of the cholinergic system. The cholinergic system is involved in a variety of behavioural functions including motor activity, sensory function, and higher executive commands. Dopaminergic neurons in the substantia nigra pars compacta (SNc) and the basal ganglia in general have long been implicated in initiation and completion of voluntary movement. Studies have shown that cholinergic neurons from two brainstem nuclei, the laterodorsal tegmental nucleus and the pedunculopontine nucleus, project onto substantia nigra dopaminergic (DA) neurons in the midbrain and release ACh, GABA or both to modulate motor behaviours. However, with prior research primarily focused on demonstrating the phenomenon of co-transmission itself, the subcellular distribution and dynamics of ACh and GABA release onto SN DA neurons receiving co-transmitted inputs largely remains to be investigated.
The present study investigates the spatial and physiological properties of ACh/GABA co- transmission from brainstem cholinergic axons synapsing onto medial SN DA neurons to understand its role in tuning the neuron’s excitatory-inhibitory balance. To that end, we developed a channelrhodopsin (ChR2)-based functional input mapping technique with high spatial resolution to probe the dendritic distribution of ACh and GABA synaptic inputs onto DA neurons in ChATcre::ChR2 mice. Using this technique, we discovered three different types of monosynaptic inputs from cholinergic axons onto DA cells: co-transmitted ACh/GABA, GABA only, and ACh only. Furthermore, we revealed a somatodendritic patterning of cholinergic input distribution onto DA cells with a predominant GABA conductance along the lateral dendrites and a soma-centered mix ACh/GABA transmission. Physiological findings were corroborated using immunolabeling against VGAT and VAChT, which showed many closely spatially clustered ACh and GABA- specific cholinergic terminals and few truly colocalized VAChT and VGAT terminals. This result revealed that true co-transmission represents a minority of the presynaptic mode of release from cholinergic axons onto medial SN DA neurons, and that the majority actually share closely spatially clustered ACh and GABA-specific cholinergic terminals.
To investigate the dynamic properties of soma-centered ACh/GABA transmission, we restricted our stimulation field to the cell body to measure the contribution of nAChR and GABAR-mediated conductances without recruiting the lateralized population of primary GABA inputs. We then employed a deconvolution method to understand the relative plasticity of contributions of nAChRs and GABARs to ACh/GABA transmission onto DA cells. We confirmed an initial dominant GABAergic component of ACh/GABA transmission that was previously reported. However, we found that the GABAergic contribution had a greater decay compared to the ACh component with repeated stimulations. As such the predominant initial inhibition is followed by a subsequent equalization of excitatory and inhibitory conductances. Finally, we performed similar experiments to compare the short-term plasticity of the isolated GABA conductance during 15 Hz stimulation between the populations of mix ACh/GABA inputs proximally and the population of primary GABA inputs found on the lateral dendrites 160 μm from the cell body. Interestingly, the lateral GABA component was more sustained across repeated stimulations compared to the proximal GABA conductance, suggesting a differential contribution to excitation/inhibition balance by spatially distributed populations of ACh and GABA inputs from cholinergic axons onto the dendrites of medial SN DA neurons. To our knowledge, this is the first study to examine the distribution and dynamics of ACh/GABA transmission onto midbrain DA system using fine-scale ChR2-assisted subcellular input mapping and conductance deconvolution.Graduate
2022-04-12
36
Yang, Ming, et 明揚. « Reversal of Autistic-like Behaviors in the Cav3.2 Knockout Mice by Enhancing GABAergic Transmission ». Thesis, 2017. http://ndltd.ncl.edu.tw/handle/zhsfx4.
Texte intégral
37
Mei-Sen et 陳美森. « Role of GABAergic transmission in the vesicovascular reflex in normal and neonatal capsaicin-treated rats ». Thesis, 2005. http://ndltd.ncl.edu.tw/handle/76884605765604105745.
Texte intégralRésumé :
碩士中山醫學大學
醫學研究所
93
Role of GABAergic transmission in the vesicovascular reflex in normal and neonatal capsaicin-treated rats To clarify the effect of GABAergic transmission in the vesico-vascular reflex (VVR). We investigated changes in blood pressure (BP) during bladder isovolumic contractions in normal and neonatal capsaicin-treated rats. In normal rats, intrathecal injection of GABA (20
38
Werner, Christian. « Effect of autoantibodies targeting amphiphysin or glutamate decarboxylase 65 on synaptic transmission of GABAergic neurons ». Doctoral thesis, 2014. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-105648.
Texte intégralRésumé :
The number of newly detected autoantibodies (AB) targeting synaptic proteins in neurological disorders of the central nervous system (CNS) is steadily increasing. Direct interactions of AB with their target antigens have been shown in first studies but the exact pathomecha-nisms for most of the already discovered AB are still unclear. The present study investigates pathophysiological mechanisms of AB-fractions that are associated with the enigmatic CNS disease Stiff person syndrome (SPS) and target the synaptically located proteins amphiphysin or glutamate decarboxylase 65 (GAD65). In the first part of the project, effects of AB to the presynaptic endocytic protein amphiphysin were investigated. Ultrastructural investigations of spinal cord presynaptic boutons in an es-tablished in-vivo passive-transfer model after intrathecal application of human anti-amphiphysin AB showed a defect of endocytosis. This defect was apparent at high synaptic activity and was characterized by reduction of the synaptic vesicle pool, clathrin coated vesi-cles (CCVs), and endosome like structures (ELS) in comparison to controls. Molecular inves-tigation of presynaptic boutons in cultured murine hippocampal neurons with dSTORM microscopy after pretreatment with AB to amphiphysin revealed that marker proteins involved in vesicle exocytosis (synaptobrevin 2 and synaptobrevin 7) had an altered expression in GA-BAergic presynapses. Endophilin, a direct binding partner of amphiphysin also displayed a disturbed expression pattern. Together, these results point towards an anti-amphiphysin AB-induced defective organization in GABAergic synapses and a presumably compensatory rearrangement of proteins responsible for CME. In the second part, functional consequences of SPS patient derived IgG fractions containing AB to GAD65, the rate limiting enzyme for GABA synthesis, were investigated by patch clamp electrophysiology and immunohistology. GABAergic neurotransmission at low and high activity as well as short term plasticity appeared normal but miniature synaptic potentials showed an enhanced frequency with constant amplitudes. SPS patient IgG after preabsorption of GAD65-AB using recombinant GAD65 still showed specific synaptic binding to neu-rons and brain slices supporting the hypothesis that additional, not yet characterized AB are present in patient IgG responsible for the exclusive effect on frequency of miniature potentials. In conclusion, the present thesis uncovered basal pathophysiological mechanisms underlying paraneoplastic SPS induced by AB to amphiphysin leading to disturbed presynaptic architec-ture. In idiopathic SPS, the hypothesis of a direct pathophysiological role of AB to GAD65 was not supported and additional IgG AB are suspected to induce distinct synaptic malfunctionDie Anzahl neu charakterisierter Autoantikörper (AAK) gegen synaptische Proteine bei Er-krankungen des zentralen Nervensystems (ZNS) ist stetig wachsend. Direkte Interaktionen der AAK mit ihren Zielantigenen konnten in ersten Studien belegt werden, jedoch besteht weiterhin Unklarheit über die exakten zugrunde liegenden Pathomechanismen. In der vorliegenden Arbeit wurden pathophysiologische Mechanismen von AAK gegen die synaptisch lokalisierten Proteine Amphiphysin und Glutamatdecarboxylase 65 (GAD65) untersucht, die mit der ZNS Erkrankung Stiff Person Syndrom (SPS) assoziiert sind. Im ersten Projektteil wurden die Effekte von AAK gegen das Endozytoseprotein Amphiphysin analysiert: in einem etablierten in-vivo Tiermodell konnten nach intrathekalem passiven Transfer von AAK gegen Amphiphysin ultrastrukturelle Untersuchungen von präsynaptischen Terminalen im Rückenmark eine Störung der Endozytose aufzeigen. Dieser Defekt, der bei hoher synaptischer Aktivität eintrat, war durch eine Verminderung synaptischen Vesikelpools, Clathrin-ummantelter Vesikel und endosomähnlicher Strukturen charakterisiert. Molekulare Untersuchungen präsynaptischer Terminale kultivierter hippokampaler Zellkulturen mit dSTORM Mikroskopie zeigten, dass an der Exozytose beteiligte synaptische Vesikelproteine (Synaptobrevin 2 und Synaptobrevin 7) ein verändertes Expressionsmuster innerhalb GA-BAerger Synapsen aufweisen. Die Expression von Endophilin, einem direkten Bindungs-partner von Amphiphysin, war ebenso verändert. Zusammengefasst weisen diese Ergebnis-se auf einen Organisationsdefekt GABAerger Synapsen hin, die durch anti-Amphiphysin AAK induziert sind und eine kompensatorische Umverteilung von Endozytoseproteinen vermuten lassen. Im zweiten Teil der Arbeit wurden die funktionellen Effekte von SPS AAK gegen GAD65, dem geschwindigkeitsbestimmenden Enzym der GABA-Synthese, mittels Patch-Clamp Mes-sungen und Immunhistologie untersucht. Die GABAerge synaptische Übertragung bei niedri-ger als auch hoher synaptischer Aktivität sowie die synaptische Kurzzeitplastizität wurden durch die IgG Fraktionen mit GAD65-AAK nicht beeinträchtigt. Die Frequenz von GABAergen Miniaturpotentialen war jedoch bei ansonsten gleichbleibender Amplitude erhöht. SPS-Patienten-IgG zeigte allerdings auch nach Präabsorbtion von GAD65-AAK mit Hilfe von rekombinanten GAD65 eine spezifische Anfärbung neuronaler Synapsen, was die Hypothese von weiteren, funktionell wirksamen, aber noch nicht identifizierten AAK im Patienten-IgG unterstützt. Zusammenfassend konnten in der vorliegenden Arbeit grundlegende pathophysiologische Mechanismen aufgezeigt werden, wie pathogene Antikörper gegen Amphiphysin die Struktur präsynaptischer Boutons beeinträchtigen können. Im Falle des idiopathischen SPS konnte keine unterstützenden Befunde für die Hypothese einer direkten pathophysiologischen Rolle von GAD65 AAK erhoben werden. Nach den vorliegenden Ergebnissen wird das Vorhandensein weiterer, derzeit noch nicht beschriebener IgG AAK postuliert, die die synaptische Fehlfunktion erklären können
39
Chudomel, Ondřej. « Age and sex differences in GABAergic transmission in the substantia nigra pars reticulata in the rat ». Doctoral thesis, 2016. http://www.nusl.cz/ntk/nusl-348939.
Texte intégralRésumé :
Many experimental as well as clinical studies have shown that subcortical neuronal circuitries including the anterior part of the substantia nigra pars reticulata (SNR) are closely involved in the control of seizures propagation and termination. In vivo studies in rats demonstrated that inhibition of the GABAergic SNRA electrical output increases the seizure threshold in the flurothyl model of generalized clonic seizures. The anticonvulsant properties of the SNRA are largely age- and sex-depended. In the current experiments were used 3 age groups of Sprague Dawley rats (PN5-9, PN11-16 and PN25-32 days, PN = postnatal) to study GABAergic inhibition. Two types of GABAergic inhibition were studied: a) a synaptic inhibition, which is generated by α1 and α3-containing GABAARs and b) a tonic inhibition mediated by extrasynaptic δ subunit-containing GABAARs. Immunohistochemistry showed that the α1 subunit expression was generally more abundant in adult rats and females while the α3 subunit dominated in the early development and gradually decreased by the age of PN30. The more α1 subunit was expressed the faster were the kinetics, higher the mean amplitudes and frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs). The α subunit subtype underlies sensitivity to zolpidem, which preferentially...
40
Engler, Birgit. « Wirkung von Cannabinoiden auf die GABAerge Neurotransmission zwischen Caudato-Putamen und Globus pallidus / ». 2005. http://www.gbv.de/du/services/toc/bs/493375503.
Texte intégral
41
Astori, Simone [Verfasser]. « Modulation of GABAergic transmission in the cerebellar stellate cell network by neurotransmitter spillover and synaptic cross talk / presented by Simone Astori ». 2006. http://d-nb.info/982426062/34.
Texte intégral
42
Keipert, Christine [Verfasser]. « Untersuchungen zur muskarinischen Modulation der GABAergen Transmission im Colliculus inferior der juvenilen Ratte / von Christine Keipert ». 2006. http://d-nb.info/978096282/34.
Texte intégral
43
Chang, Ting-Hsuan Daniel, et 張珽瑄. « Comparison of Transmission at Synapses of Layers 2/3 Input onto Layer 5 Pyramidal and GABAergic Neurons in Rostral Agranular Insular Cortex ». Thesis, 2016. http://ndltd.ncl.edu.tw/handle/93585570272002491439.
Texte intégralRésumé :
碩士國立臺灣大學
生命科學系
104
It has been shown that inhibition or lesion of the rostral agranular insular cortex (RAIC) results in analgesia, it suggests that RAIC tonically produces hyperalgesia signal. RAIC is a cortical area where nociceptive output originates, and it has been reported to activate in chronic pain perception. It’s believed that chronic pain is associated with the long-term change in synaptic plasticity. Moreover, the imbalance of excitatory and inhibitory (E/I) synaptic signaling in neural circuits is responsible to modulate synaptic plasticity in certain behavior disorders. In our lab, previous study had reported that the induction of chronic pain induced differential activation in pyramidal cells and GABAergic neurons in RAIC. We propose here that E/I imbalance in RAIC may contribute to the increased cortical output of nociceptive signal in chronic pain. To test this possibility, we compared synaptic transmission of layers 2/3 (L2/3) inputs onto layer 5 (L5) pyramidal cells (PC), which are the descending projection neurons, and onto local GABAergic interneurons (IntN) in RAIC. We performed dual-patch recording from a paired IntN-PC in layer 5, and elicited EPSC by putting an electrode in layer 2/3. We found functional connectivity in 34.2% of all recorded IntN-PC pairs. There was no significant difference in data sampled from IntN-PC pairs with and without functional connectivity, and all data were pooled. Our data showed no significant difference in paring-pulse ratio between transmission at L2/3-PC synapses and at L2/3-IntN synapses. L2/3-IntN seemed to have higher releasing probability than L2/3-PC synapse in quantum study. The ratio of NMDA and non-NMDA EPSCs component was larger at L2/3-PC synapses than at L2/3-IntN synapses. Furthermore, the rising and decay of EPSCs were much faster at L2/3-IntN synapse than at L2/3-PC synapse. We further examined the modulation of pERK on IntN-PC pairs by applying PKC activator Phorbol 12,13- diacetate (PDA). PDA enhanced the postsynaptic currents at L2/3-PC synapses and L2/3- IntN synapses. The further issue of chronic pain model is under studying.
44
Lin, Bei-Xuan, et 林蓓萱. « Synaptic Transmission of GABAergic Interneurons on Layer 5 Pyramidal Neurons in the Rostral Agranular Insular Cortex of Control and Muscle Pain Mice ». Thesis, 2017. http://ndltd.ncl.edu.tw/handle/45mghz.
Texte intégralRésumé :
碩士國立臺灣大學
生命科學系
105
It has been well demonstrated that the change of synaptic efficacy in neurocircuit of brain pain matrix is a cellular substrate for behavior hypersensitivity in animals with chronic pain. While most of previous studies focus on transmission at synapses between nociceptive inputs and principal neurons, the role of local GABAergic interneurons (IntNs) receives less attention. I address this issue by using the acid-induced muscle pain animal model (AIMP model) in mice and focusing on the rostral agranular insular cortex (RAIC). The RAIC is an important component of brain pain matrix as this cortical area is shown to tonically produce hyperalgesia signal and is a cortical area where nociceptive output originates. We propose that repeated acid saline injection may trigger a plastic change in synaptic efficacy of GABAergic IntNs onto pyramidal neurons (PNs) and cause an excitatory/inhibitory imbalance in neurocircuit in RAIC, which in turn alters cortical output of nociceptive signal in chronic pain. To test this possibility, dual-patch recording from a pair of IntN-PN in layer 5 was initially used to record unitary inhibitory postsynaptic current (IPSC) in previous experiments of our lab, and found that only 30% of all recorded IntN-PN pairs showed functional connectivity. To increase successful rate, here I employ optogenetic method to selectively active GABAergic IntNs. I injected a cre-dependent AAV that carries eYFP and channelrhodopsin2 sequences into RAIC in transgenic mice, in which the promoter of vesicular-GABA-transporter controls expression of cre recombinase. The animals were killed 2-3 weeks after AAV injection for brain slice preparation and whole-cell patch recording was made from PNs. Illuminating the slice with a single blue-light pulse (2 ms) evoked inhibitory postsynaptic current (IPSC) in PNs that was blocked by 20 uM bicuculline, a GABAA receptor antagonist. The paired-pulse ratio of the IPSC significantly reduced from 0.66 ± 0.10 (n = 13) in control mice to 0.37 ± 0.03 (n = 12) in muscle pain mice (P < 0.05; Mann-Whitney Test); the quantal size of the IPSC was significantly increased from 12.88 ± 1.22 pA (n = 13) in control mice to 18.82 ± 1.91 (n = 12) pA in muscle pain mice (P < 0.05; Mann-Whitney Test). These results show potential changes in synaptic function of GABAergic IntNs onto PNs in RAIC in chronic pain condition.
45
Kirmse, Knut [Verfasser]. « Die GABAerge synaptische Transmission auf Cajal-Retzius-Zellen des visuellen Kortex der Maus / von Knut Kirmse ». 2007. http://d-nb.info/987994190/34.
Texte intégral
46
Xing, Paul. « Implication de Syngap1 dans la transmission GABAergique et la plasticité synaptique ». Thèse, 2015. http://hdl.handle.net/1866/13793.
Texte intégralRésumé :
La déficience intellectuelle affecte de 1 à 3% de la population mondiale, ce qui en fait le trouble cognitif le plus commun de l’enfance. Notre groupe à découvert que des mutations dans le gène SYNGAP1 sont une cause fréquente de déficience intellectuelle non-syndromique, qui compte pour 1-3% de l’ensemble des cas. À titre d’exemple, le syndrome du X fragile, qui est la cause monogénique la plus fréquente de déficience intellectuelle, compte pour environ 2% des cas. Plusieurs patients affectés au niveau de SYNGAP1 présentent également des symptômes de l’autisme et d’une forme d’épilepsie. Notre groupe a également montré que SYNGAP1 cause la déficience intellectuelle par un mécanisme d’haploinsuffisance. SYNGAP1 code pour une protéine exprimée exclusivement dans le cerveau qui interagit avec la sous-unité GluN2B des récepteurs glutamatergique de type NMDA (NMDAR). SYNGAP1 possède une activité activatrice de Ras-GTPase qui régule négativement Ras au niveau des synapses excitatrices.
Les souris hétérozygotes pour Syngap1 (souris Syngap1+/-) présentent des anomalies de comportement et des déficits cognitifs, ce qui en fait un bon modèle d’étude. Plusieurs études rapportent que l’haploinsuffisance de Syngap1 affecte le développement cérébral en perturbant l’activité et la plasticité des neurones excitateurs. Le déséquilibre excitation/inhibition est une théorie émergente de l’origine de la déficience intellectuelle et de l’autisme. Cependant, plusieurs groupes y compris le nôtre ont rapporté que Syngap1 est également exprimé dans au moins une sous-population d’interneurones GABAergiques. Notre hypothèse était donc que l’haploinsuffisance de Syngap1 dans les interneurones contribuerait en partie aux déficits cognitifs et au déséquilibre d’excitation/inhibition observés chez les souris Syngap1+/-.
Pour tester cette hypothèse, nous avons généré un modèle de souris transgéniques dont l’expression de Syngap1 a été diminuée uniquement dans les interneurones dérivés des éminences ganglionnaires médianes qui expriment le facteur de transcription Nkx2.1 (souris Tg(Nkx2,1-Cre);Syngap1). Nous avons observé une diminution des courants postsynaptiques inhibiteurs miniatures (mIPSCs) au niveau des cellules pyramidales des couches 2/3 du cortex somatosensoriel primaire (S1) et dans le CA1 de l’hippocampe des souris Tg(Nkx2,1-Cre);Syngap1. Ces résultats supportent donc l’hypothèse selon laquelle la perte de Syngap1 dans les interneurones contribue au déséquilibre d’excitation/inhibition. De manière intéressante, nous avons également observé que les courants postsynaptiques excitateurs miniatures (mEPSCs) étaient augmentés dans le cortex S1, mais diminués dans le CA1 de l’hippocampe.
Par la suite, nous avons testé si les mécanismes de plasticité synaptique qui sous-tendraient l’apprentissage étaient affectés par l’haploinsuffisance de Syngap1 dans les interneurones. Nous avons pu montrer que la potentialisation à long terme (LTP) NMDAR-dépendante était diminuée chez les souris Tg(Nkx2,1-Cre);Syngap1, sans que la dépression à long terme (LTD) NMDAR-dépendante soit affectée. Nous avons également montré que l’application d’un bloqueur des récepteurs GABAA renversait en partie le déficit de LTP rapporté chez les souris Syngap1+/-, suggérant qu’un déficit de désinhibition serait présent chez ces souris.
L’ensemble de ces résultats supporte un rôle de Syngap1 dans les interneurones qui contribue aux déficits observés chez les souris affectées par l’haploinsuffisance de Syngap1.Intellectual disability affects 1-3% of the world population, which make it the most common cognitive disorder of childhood. Our group discovered that mutation in the SYNGAP1 gene was a frequent cause of non-syndromic intellectual disability, accounting for 1-3% of the cases. For example, the fragile X syndrome, which is the most common monogenic cause of intellectual disability, accounts for 2% of all cases. Some patients affected by SYNGAP1 also showed autism spectrum disorder and epileptic seizures. Our group also showed that mutations in SYNGAP1 caused intellectual disability by an haploinsufficiency mechanism. SYNGAP1 codes for a protein expressed only in the brain which interacts with the GluN2B subunit of NMDA glutamatergic receptors (NMDAR). SYNGAP1 possesses a Ras-GAP activating activity which negatively regulates Ras at excitatory synapses. Heterozygote mice for Syngap1 (Syngap1+/- mice) show behaviour abnormalities and learning deficits, which makes them a good model of intellectual disability. Some studies showed that Syngap1 affects the brain development by perturbing the activity and plasticity of excitatory neurons. The excitatory/inhibitory imbalance is an emerging theory of the origin of intellectual disability and autism. However, some groups including ours, showed that Syngap1 is expressed in at least a subpopulation of GABAergic interneurons. Therefore, our hypothesis was that Syngap1 happloinsufficiency in interneurons contributes in part to the cognitive deficits and excitation/inhibition imbalance observed in Syngap1+/- mice. To test this hypothesis, we generated a transgenic mouse model where Syngap1 expression was decreased only in GABAergic interneurons derived from the medial ganglionic eminence, which expresses the transcription factor Nkx2.1 (Tg(Nkx2,1-Cre);Syngap1 mouse). We showed that miniature inhibitory postsynaptic currents (mIPSCs) were decreased in pyramidal cells in layers 2/3 in primary somatosensory cortex (S1) and in CA1 region of the hippocampus of Tg(Nkx2,1-Cre);Syngap1 mice. Those results suggest that Syngap1 haploinsufficiency in GABAergic interneurons contributes in part to the excitation/inhibition imbalance observed in Syngap1+/- mice. Interestingly, we also observed that miniature excitatory postsynaptic currents (mEPSCs) were increased in cortex S1 but decreased in CA1 region of the hippocampus. We further tested whether synaptic plasticity mechanisms that are thought to underlie learning and memory were affected by Syngap1 haploinsufficiency in GABAergic interneurons. We showed that NMDAR-dependent long-term potentiation (LTP) but not NMDAR-dependent long-term depression (LTD) was decreased in Tg(Nkx2,1-Cre);Syngap1 mice. We also showed that GABAA receptor blockade rescued in part the LTP deficit in Syngap1+/- mice, suggesting that a disinhibition deficit is present in these mice. Altogether, the results support a functional role of Syngap1 in GABAergic interneurons, which may in turn contributes to the deficit observed in Syngap1+/- mice.
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Walter, Jan [Verfasser]. « Glutamaterge Modulation der GABAergen synaptischen Transmission durch metabotrope Glutamatrezeptoren der Gruppe I sowie deren Einfluss auf die Synaptogenese in Hirnschnittpräparaten / von Jan Walter ». 2006. http://d-nb.info/983750432/34.
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