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1
Tonini, Raffaella, Teresa Ferraro, Marisol Sampedro-Castañeda, Anna Cavaccini, Martin Stocker, Christopher D. Richards, and Paola Pedarzani. "Small-conductance Ca2+-activated K+ channels modulate action potential-induced Ca2+ transients in hippocampal neurons." Journal of Neurophysiology 109, no. 6 (March 15, 2013): 1514–24. http://dx.doi.org/10.1152/jn.00346.2012.
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In hippocampal pyramidal neurons, voltage-gated Ca2+ channels open in response to action potentials. This results in elevations in the intracellular concentration of Ca2+ that are maximal in the proximal apical dendrites and decrease rapidly with distance from the soma. The control of these action potential-evoked Ca2+ elevations is critical for the regulation of hippocampal neuronal activity. As part of Ca2+ signaling microdomains, small-conductance Ca2+-activated K+ (SK) channels have been shown to modulate the amplitude and duration of intracellular Ca2+ signals by feedback regulation of synaptically activated Ca2+ sources in small distal dendrites and dendritic spines, thus affecting synaptic plasticity in the hippocampus. In this study, we investigated the effect of the activation of SK channels on Ca2+ transients specifically induced by action potentials in the proximal processes of hippocampal pyramidal neurons. Our results, obtained by using selective SK channel blockers and enhancers, show that SK channels act in a feedback loop, in which their activation by Ca2+ entering mainly through L-type voltage-gated Ca2+ channels leads to a reduction in the subsequent dendritic influx of Ca2+. This underscores a new role of SK channels in the proximal apical dendrite of hippocampal pyramidal neurons.
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Quach, Tam, Nathalie Auvergnon, Rajesh Khanna, Marie-Françoise Belin, Papachan Kolattukudy, Jérome Honnorat, and Anne-Marie Duchemin. "Opposing Morphogenetic Defects on Dendrites and Mossy Fibers of Dentate Granular Neurons in CRMP3-Deficient Mice." Brain Sciences 8, no. 11 (November 3, 2018): 196. http://dx.doi.org/10.3390/brainsci8110196.
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Collapsin response mediator proteins (CRMPs) are highly expressed in the brain during early postnatal development and continue to be present in specific regions into adulthood, especially in areas with extensive neuronal plasticity including the hippocampus. They are found in the axons and dendrites of neurons wherein they contribute to specific signaling mechanisms involved in the regulation of axonal and dendritic development/maintenance. We previously identified CRMP3’s role on the morphology of hippocampal CA1 pyramidal dendrites and hippocampus-dependent functions. Our focus here was to further analyze its role in the dentate gyrus where it is highly expressed during development and in adults. On the basis of our new findings, it appears that CRMP3 has critical roles both in axonal and dendritic morphogenesis of dentate granular neurons. In CRMP3-deficient mice, the dendrites become dystrophic while the infrapyramidal bundle of the mossy fiber shows aberrant extension into the stratum oriens of CA3. This axonal misguided projection of granular neurons suggests that the mossy fiber-CA3 synaptic transmission, important for the evoked propagation of the activity of the hippocampal trisynaptic circuitry, may be altered, whereas the dystrophic dendrites may impair the dynamic interactions with the entorhinal cortex, both expected to affect hippocampal function.
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Chen, Chih-Ming, Lauren L. Orefice, Shu-Ling Chiu, Tara A. LeGates, Samer Hattar, Richard L. Huganir, Haiqing Zhao, Baoji Xu, and Rejji Kuruvilla. "Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice." Proceedings of the National Academy of Sciences 114, no. 4 (January 9, 2017): E619—E628. http://dx.doi.org/10.1073/pnas.1615792114.
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Stability of neuronal connectivity is critical for brain functions, and morphological perturbations are associated with neurodegenerative disorders. However, how neuronal morphology is maintained in the adult brain remains poorly understood. Here, we identify Wnt5a, a member of the Wnt family of secreted morphogens, as an essential factor in maintaining dendritic architecture in the adult hippocampus and for related cognitive functions in mice. Wnt5a expression in hippocampal neurons begins postnatally, and its deletion attenuated CaMKII and Rac1 activity, reduced GluN1 glutamate receptor expression, and impaired synaptic plasticity and spatial learning and memory in 3-mo-old mice. With increased age, Wnt5a loss caused progressive attrition of dendrite arbors and spines in Cornu Ammonis (CA)1 pyramidal neurons and exacerbated behavioral defects. Wnt5a functions cell-autonomously to maintain CA1 dendrites, and exogenous Wnt5a expression corrected structural anomalies even at late-adult stages. These findings reveal a maintenance factor in the adult brain, and highlight a trophic pathway that can be targeted to ameliorate dendrite loss in pathological conditions.
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Komendantov, Alexander O., and Giorgio A. Ascoli. "Dendritic Excitability and Neuronal Morphology as Determinants of Synaptic Efficacy." Journal of Neurophysiology 101, no. 4 (April 2009): 1847–66. http://dx.doi.org/10.1152/jn.01235.2007.
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The ability to trigger neuronal spiking activity is one of the most important functional characteristics of synaptic inputs and can be quantified as a measure of synaptic efficacy (SE). Using model neurons with both highly simplified and real morphological structures (from a single cylindrical dendrite to a hippocampal granule cell, CA1 pyramidal cell, spinal motoneuron, and retinal ganglion neurons) we found that SE of excitatory inputs decreases with the distance from the soma and active nonlinear properties of the dendrites can counterbalance this global effect of attenuation. This phenomenon is frequency dependent, with a more prominent gain in SE observed at lower levels of background input–output neuronal activity. In contrast, there are no significant differences in SE between passive and active dendrites under higher frequencies of background activity. The influence of the nonuniform distribution of active properties on SE is also more prominent at lower background frequencies. In models with real morphologies, the effect of active dendritic conductances becomes more dramatic and inverts the SE relationship between distal and proximal locations. In active dendrites, distal synapses have higher efficacy than that of proximal ones because of arising dendritic spiking in thin branches with high-input resistance. Lower levels of dendritic excitability can make SE independent of the distance from the soma. Although increasing dendritic excitability may boost SE of distal synapses in real neurons, it may actually reduce overall SE. The results are robust with respect to morphological variation and biophysical properties of the model neurons. The model of CA1 pyramidal cell with realistic distributions of dendritic conductances demonstrated important roles of hyperpolarization-activated (h-) current and A-type K+ current in controlling the efficacy of single synaptic inputs and overall SE differently in basal and apical dendrites.
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Ashhad, Sufyan, and Rishikesh Narayanan. "Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons." Proceedings of the National Academy of Sciences 113, no. 23 (May 23, 2016): E3280—E3289. http://dx.doi.org/10.1073/pnas.1522180113.
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An important consequence of gliotransmission, a signaling mechanism that involves glial release of active transmitter molecules, is its manifestation as N-methyl-d-aspartate receptor (NMDAR)-dependent slow inward currents in neurons. However, the intraneuronal spatial dynamics of these events or the role of active dendrites in regulating their amplitude and spatial spread have remained unexplored. Here, we used somatic and/or dendritic recordings from rat hippocampal pyramidal neurons and demonstrate that a majority of NMDAR-dependent spontaneous slow excitatory potentials (SEP) originate at dendritic locations and are significantly attenuated through their propagation across the neuronal arbor. We substantiated the astrocytic origin of SEPs through paired neuron–astrocyte recordings, where we found that specific infusion of inositol trisphosphate (InsP3) into either distal or proximal astrocytes enhanced the amplitude and frequency of neuronal SEPs. Importantly, SEPs recorded after InsP3 infusion into distal astrocytes exhibited significantly slower kinetics compared with those recorded after proximal infusion. Furthermore, using neuron-specific infusion of pharmacological agents and morphologically realistic conductance-based computational models, we demonstrate that dendritically expressed hyperpolarization-activated cyclic-nucleotide–gated (HCN) and transient potassium channels play critical roles in regulating the strength, kinetics, and compartmentalization of neuronal SEPs. Finally, through the application of subtype-specific receptor blockers during paired neuron–astrocyte recordings, we provide evidence that GluN2B- and GluN2D-containing NMDARs predominantly mediate perisomatic and dendritic SEPs, respectively. Our results unveil an important role for active dendrites in regulating the impact of gliotransmission on neurons and suggest astrocytes as a source of dendritic plateau potentials that have been implicated in localized plasticity and place cell formation.
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Srivastava, U. C., Durgesh Singh, Prashant Kumar, and Sippy Singh. "Neuronal diversity and their spine density in the hippocampal complex of the House Crow (Corvus splendens), a food-storing bird." Canadian Journal of Zoology 94, no. 8 (August 2016): 541–53. http://dx.doi.org/10.1139/cjz-2015-0260.
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Hippocampus, one of the parts included in the limbic system, is involved in various functions such as learning, memory, food-storing behavior, and sexual discrimination. Neuronal classes of the hippocampal complex in food-storing birds have been also reported, but the study lacks details pertaining to neuronal characteristics and the spine density of the neurons in different subfields of the hippocampus. Hence, the present study was undertaken with the aim to explore the morphology of neurons and the spines present on their dendrites within the hippocampal complex of the House Crow (Corvus splendens Vieillot, 1817), a food-storing Indian bird, and to compare it with previously reported nonfood-storing bird species. It was observed that the hippocampus of C. splendens harbors diverse neuronal classes with substantial percentages of pyramidal neurons, well-developed local circuit neurons, and high spine density. All these neuronal specializations in C. splendens can be related with the food-storing behavior of the bird, which itself is an advantage over nonfood-storing birds.
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Flood, Dorothy G., and Paul D. Coleman. "Failed Compensatory Dendritic Growth as a Pathophysiological Process in Alzheimer's Disease." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 13, S4 (November 1986): 475–79. http://dx.doi.org/10.1017/s031716710003715x.
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Abstract:In normal human aging the remaining neurons of two areas of the hippocampal region have been found to compensate for age-related neuronal loss by proliferating new dendrites. In Alzheimer's disease (AD) the layer II pyramidal neurons of the parahippocampal gyrus fail to show this compensatory response, in spite of a probable, exaggerated disease-related loss of neurons. In AD the dentate gyrus granule cells of the hippocampus also show a reduced amount of the compensatory response. This failure of the AD brain to show the normal compensatory plastic response, seen in normal aging as dendritic growth, may be viewed as one of the pathophysiological processes of the disease.
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Ishikawa, Tomoe, and Yuji Ikegaya. "Locally sequential synaptic reactivation during hippocampal ripples." Science Advances 6, no. 7 (February 2020): eaay1492. http://dx.doi.org/10.1126/sciadv.aay1492.
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The sequential reactivation of memory-relevant neuronal ensembles during hippocampal sharp-wave (SW) ripple oscillations reflects cognitive processing. However, how a downstream neuron decodes this spatiotemporally organized activity remains unexplored. Using subcellular calcium imaging from CA1 pyramidal neurons in ex vivo hippocampal networks, we discovered that neighboring spines are activated serially along dendrites toward or away from cell bodies. Sequential spine activity was engaged repeatedly in different SWs in a complex manner. In a single SW event, multiple sequences appeared discretely in dendritic trees, but overall, sequences occurred preferentially in some dendritic branches. Thus, sequential replays of multineuronal spikes are distributed across several compartmentalized dendritic foci of a postsynaptic neuron, with their spatiotemporal features preserved.
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Craig, Emma, Christopher M. Dillingham, Michal M. Milczarek, Heather M. Phillips, Moira Davies, James C. Perry, and Seralynne D. Vann. "Lack of change in CA1 dendritic spine density or clustering in rats following training on a radial-arm maze task." Wellcome Open Research 5 (April 14, 2020): 68. http://dx.doi.org/10.12688/wellcomeopenres.15745.1.
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Background: Neuronal plasticity is thought to underlie learning and memory formation. The density of dendritic spines in the CA1 region of the hippocampus has been repeatedly linked to mnemonic processes. Both the number and spatial location of the spines, in terms of proximity to nearest neighbour, have been implicated in memory formation. To examine how spatial training impacts synaptic structure in the hippocampus, Lister-Hooded rats were trained on a hippocampal-dependent spatial task in the radial-arm maze. Methods: One group of rats were trained on a hippocampal-dependent spatial task in the radial arm maze. Two further control groups were included: a yoked group which received the same sensorimotor stimulation in the radial-maze but without a memory load, and home-cage controls. At the end of behavioural training, the brains underwent Golgi staining. Spines on CA1 pyramidal neuron dendrites were imaged and quantitatively assessed to provide measures of density and distance from nearest neighbour. Results: There was no difference across behavioural groups either in terms of spine density or in the clustering of dendritic spines. Conclusions: Spatial learning is not always accompanied by changes in either the density or clustering of dendritic spines on the basal arbour of CA1 pyramidal neurons when assessed using Golgi imaging.
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Craig, Emma, Christopher M. Dillingham, Michal M. Milczarek, Heather M. Phillips, Moira Davies, James C. Perry, and Seralynne D. Vann. "Lack of change in CA1 dendritic spine density or clustering in rats following training on a radial-arm maze task." Wellcome Open Research 5 (May 15, 2020): 68. http://dx.doi.org/10.12688/wellcomeopenres.15745.2.
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Background: Neuronal plasticity is thought to underlie learning and memory formation. The density of dendritic spines in the CA1 region of the hippocampus has been repeatedly linked to mnemonic processes. Both the number and spatial location of the spines, in terms of proximity to nearest neighbour, have been implicated in memory formation. To examine how spatial training impacts synaptic structure in the hippocampus, Lister-Hooded rats were trained on a hippocampal-dependent spatial task in the radial-arm maze. Methods: One group of rats were trained on a hippocampal-dependent spatial task in the radial arm maze. Two further control groups were included: a yoked group which received the same sensorimotor stimulation in the radial-maze but without a memory load, and home-cage controls. At the end of behavioural training, the brains underwent Golgi staining. Spines on CA1 pyramidal neuron dendrites were imaged and quantitatively assessed to provide measures of density and distance from nearest neighbour. Results: There was no difference across behavioural groups either in terms of spine density or in the clustering of dendritic spines. Conclusions: Spatial learning is not always accompanied by changes in either the density or clustering of dendritic spines on the basal arbour of CA1 pyramidal neurons when assessed using Golgi imaging.
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Carnevale, Nicholas T., Kenneth Y. Tsai, Brenda J. Claiborne, and Thomas H. Brown. "Comparative Electrotonic Analysis of Three Classes of Rat Hippocampal Neurons." Journal of Neurophysiology 78, no. 2 (August 1, 1997): 703–20. http://dx.doi.org/10.1152/jn.1997.78.2.703.
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Carnevale, Nicholas T., Kenneth Y. Tsai, Brenda J. Claiborne, and Thomas H. Brown. Comparative electrotonic analysis of three classes of rat hippocampal neurons. J. Neurophysiol. 78: 703–720, 1997. We present a comparative analysis of electrotonus in the three classes of principal neurons in rat hippocampus: pyramidal cells of the CA1 and CA3c fields of the hippocampus proper, and granule cells of the dentate gyrus. This analysis used the electrotonic transform, which combines anatomic and biophysical data to map neuronal anatomy into electrotonic space, where physical distance between points is replaced by the logarithm of voltage attenuation (log A). The transforms were rendered as “neuromorphic figures” by redrawing the cell with branch lengths proportional to log A along each branch. We also used plots of log A versus anatomic distance from the soma; these reveal features that are otherwise less apparent and facilitate comparisons between dendritic fields of different cells. Transforms were always larger for voltage spreading toward the soma ( V in) than away from it ( V out). Most of the electrotonic length in V out transforms was along proximal large diameter branches where signal loss for somatofugal voltage spread is greatest. In V in transforms, more of the length was in thin distal branches, indicating a steep voltage gradient for signals propagating toward the soma. All transforms lengthened substantially with increasing frequency. CA1 neurons were electrotonically significantly larger than CA3c neurons. Their V out transforms displayed one primary apical dendrite, which bifurcated in some cases, whereas CA3c cell transforms exhibited multiple apical branches. In both cell classes, basilar dendrite V out transforms were small, indicating that somatic potentials reached their distal ends with little attenuation. However, for somatopetal voltage spread, attenuation along the basilar and apical dendrites was comparable, so the V in transforms of these dendritic fields were nearly equal in extent. Granule cells were physically and electrotonically most compact. Their V out transforms at 0 Hz were very small, indicating near isopotentiality at DC and low frequencies. These transforms resembled those of the basilar dendrites of CA1 and CA3c pyramidal cells. This raises the possibility of similar functional or computational roles for these dendritic fields. Interpreting the anatomic distribution of thorny excrescences on CA3 pyramidal neurons with this approach indicates that synaptic currents generated by some mossy fiber inputs may be recorded accurately by a somatic patch clamp, providing that strict criteria on their time course are satisfied. Similar accuracy may not be achievable in somatic recordings of Schaffer collateral synapses onto CA1 pyramidal cells in light of the anatomic and biophysical properties of these neurons and the spatial distribution of synapses.
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Bancroft, Eric, Rahul Srinivasan, and Lee A. Shapiro. "Macrophage Migration Inhibitory Factor Alters Functional Properties of CA1 Hippocampal Neurons in Mouse Brain Slices." International Journal of Molecular Sciences 21, no. 1 (December 31, 2019): 276. http://dx.doi.org/10.3390/ijms21010276.
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Neuroinflammation is implicated in a host of neurological insults, such as traumatic brain injury (TBI), ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and epilepsy. The immune response to central nervous system (CNS) injury involves sequelae including the release of numerous cytokines and chemokines. Macrophage migration inhibitory factor (MIF), is one such cytokine that is elevated following CNS injury, and is associated with the prognosis of TBI, and ischemic stroke. MIF has been identified in astrocytes and neurons, and some of the trophic actions of MIF have been related to its direct and indirect actions on astrocytes. However, the potential modulation of CNS neuronal function by MIF has not yet been explored. This study tests the hypothesis that MIF can directly influence hippocampal neuronal function. MIF was microinjected into the hippocampus and the genetically encoded calcium indicator, GCaMP6f, was used to measure Ca2+ events in acute adult mouse brain hippocampal slices. Results demonstrated that a single injection of 200 ng MIF into the hippocampus significantly increased baseline calcium signals in CA1 pyramidal neuron somata, and altered calcium responses to N-methyl-d-aspartate (NMDA) + D-serine in pyramidal cell apical dendrites located in the stratum radiatum. These data are the first to show direct effects of MIF on hippocampal neurons and on NMDA receptor function. Considering that MIF is elevated after brain insults such as TBI, the data suggest that, in addition to the previously described role of MIF in astrocyte reactivity, elevated MIF can have significant effects on neuronal function in the hippocampus.
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Narayanan, Rishikesh, and Sumantra Chattarji. "Computational Analysis of the Impact of Chronic Stress on Intrinsic and Synaptic Excitability in the Hippocampus." Journal of Neurophysiology 103, no. 6 (June 2010): 3070–83. http://dx.doi.org/10.1152/jn.00913.2009.
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Dendritic atrophy and impaired long-term synaptic potentiation (LTP) are hallmarks of chronic stress-induced plasticity in the hippocampus. It has been hypothesized that these disparate structural and physiological correlates of stress lead to hippocampal dysfunction by reducing postsynaptic dendritic surface, thereby adversely affecting the availability of synaptic inputs and suppressing LTP. Here we examine the validity of this framework using biophysical models of hippocampal CA3 pyramidal neurons. To statistically match with the experimentally observed region specificity of stress-induced atrophy, we use an algorithm to systematically prune three-dimensional reconstructions of CA3 pyramidal neurons. Using this algorithm, we build a biophysically realistic computational model to analyze the effects of stress on intrinsic and synaptic excitability. We find that stress-induced atrophy of CA3 dendrites leads to an increase in input resistance, which depends exponentially on the percentage of neuronal atrophy. This increase translates directly into higher spiking frequencies in response to both somatic current injections and synaptic inputs at various locations along the dendritic arbor. Remarkably, we also find that the dendritic regions that manifest atrophy-induced synaptic hyperexcitability are governed by the region specificity of the underlying dendritic atrophy. Coupled with experimentally observed modulation of N-methyl-d-aspartate receptor currents, such hyperexcitability could tilt the balance of plasticity mechanisms in favor of synaptic potentiation over depression. Thus paradoxically, our results suggest that stress may impair hippocampal learning and memory, not by directly inhibiting LTP, but because of stress-induced facilitation of intrinsic and synaptic excitability and the consequent imbalance in bidirectional synaptic plasticity.
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Sá, Maria José, Carlos Ruela, and Maria Dulce Madeira. "Dendritic right/left asymmetries in the neurons of the human hippocampal formation: a quantitative Golgi study." Arquivos de Neuro-Psiquiatria 65, no. 4b (December 2007): 1105–13. http://dx.doi.org/10.1590/s0004-282x2007000700003.
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OBJECTIVE: To search for right/left asymmetries in the dendritic trees of the neuronal populations and in the cell-free layer volumes of the human hipoccampal formation. METHOD: In necropsic material obtained from six male individuals we performed a quantitative Golgi study of the dendritic trees of dentate granules, CA3 and CA1 pyramidal neurons and a volumetric analysis of dentate gyrus molecular layer, strata oriens plus alveus and strata lacunosum-moleculare plus radiatum of CA3 and CA1 fields. RESULTS: We found inter-hemispheric asymmetries in the dendrites trees of all neurons, reaching the significant level in the number of granule cells dendritic segments (higher in the left than in the right hemisphere), dendritic branching density of CA3 pyramidal cells and mean dendritic length of CA1 apical terminal segments (higher in the right than in the opposite side). No volumetric differences were observed. CONCLUSION: This study points to different anatomical patterns of connectivity in the hippocampal formations of both hemispheres which may underlie functional asymmetries.
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Shim, Seong S., Michael D. Hammonds, and Ronald F. Mervis. "Four weeks lithium treatment alters neuronal dendrites in the rat hippocampus." International Journal of Neuropsychopharmacology 16, no. 6 (July 1, 2013): 1373–82. http://dx.doi.org/10.1017/s1461145712001423.
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AbstractA large body of evidence from molecular, cellular and human studies suggests that lithium may enhance synaptic plasticity, which may be associated with its therapeutic efficacy. However, only a small number of studies have directly assessed this. To determine whether lithium treatment alters structural synaptic plasticity, this study examined the effect of 4 wk lithium treatment on the amount and distribution of dendrites in the dentate gyrus (DG) and hippocampal area CA1 of young adult rats. Following 4 wk lithium or control chow feeding, animals were decapitated, the hippocampi were prepared and stained using a rapid Golgi staining technique and the amount and distribution of the dendritic branching was evaluated using Sholl analyses (method of concentric circles). In the DG, lithium treatment increased the amount and distribution of dendritic branches in the proximal half of dendritic trees of the granule cells and reduced branching in the distal half. In area CA1, the same treatment also increased the number of dendritic branches in the proximal half of apical dendritic trees of CA1 pyramidal cells and reduced branching in the distal half of apical dendritic trees but had no effect on basilar dendritic trees. The lithium treatment altered the total density of dendritic trees in neither the DG nor area CA1. These findings suggest that, in the DG and apical CA1, chronic lithium treatment rearranges neuronal morphology to increase dendritic branching and distribution to where major afferent input is received.
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Letellier, Mathieu, Yun Kyung Park, Thomas E. Chater, Peter H. Chipman, Sunita Ghimire Gautam, Tomoko Oshima-Takago, and Yukiko Goda. "Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks." Proceedings of the National Academy of Sciences 113, no. 19 (April 26, 2016): E2685—E2694. http://dx.doi.org/10.1073/pnas.1523717113.
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Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-d-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca2+ channels. Intracellular infusion of NMDARs or Ca2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocyte-dependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites.
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Moreno, David G., Emma C. Utagawa, Nicoleta C. Arva, Kristian T. Schafernak, Elliott J. Mufson, and Sylvia E. Perez. "Postnatal Cytoarchitecture and Neurochemical Hippocampal Dysfunction in Down Syndrome." Journal of Clinical Medicine 10, no. 15 (July 31, 2021): 3414. http://dx.doi.org/10.3390/jcm10153414.
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Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volume, which are later associated with memory deficits, little is known about the effects of trisomy 21 on postnatal hippocampal cellular development in Down syndrome (DS). We examined postnatal hippocampal neuronal profiles from autopsies of DS and neurotypical (NTD) neonates born at 38-weeks’-gestation up to children 3 years of age using antibodies against non-phosphorylated (SMI-32) and phosphorylated (SMI-34) neurofilament, calbindin D-28k (Calb), calretinin (Calr), parvalbumin (Parv), doublecortin (DCX) and Ki-67, as well as amyloid precursor protein (APP), amyloid beta (Aβ) and phosphorylated tau (p-tau). Although the distribution of SMI-32-immunoreactive (-ir) hippocampal neurons was similar at all ages in both groups, pyramidal cell apical and basal dendrites were intensely stained in NTD cases. A greater reduction in the number of DCX-ir cells was observed in the hippocampal granule cell layer in DS. Although the distribution of Calb-ir neurons was similar between the youngest and oldest NTD and DS cases, Parv-ir was not detected. Conversely, Calr-ir cells and fibers were observed at all ages in DS, while NTD cases displayed mainly Calr-ir fibers. Hippocampal APP/Aβ-ir diffuse-like plaques were seen in DS and NTD. By contrast, no Aβ1–42 or p-tau profiles were observed. These findings suggest that deficits in hippocampal neurogenesis and pyramidal cell maturation and increased Calr immunoreactivity during early postnatal life contribute to cognitive impairment in DS.
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Shen, Hui, and Sheryl S. Smith. "Plasticity of the α4βδ GABAA receptor." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1378–84. http://dx.doi.org/10.1042/bst0371378.
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The GABAR [GABAA (γ-aminobutyric acid type A) receptor], which mediates most inhibition in the brain, is regulated homoeostatically to maintain an optimal level of neuronal excitability. In particular, the α4βδ subtype of the GABAR plays a pivotal role in this regulation. This receptor, which is expressed extrasynaptically on the dendrites, normally has low expression in the brain, but displays a remarkable degree of plasticity. It can also be a sensitive target for endogenous neurosteroids such as THP (3α-hydroxy-5[α]β-pregnan-20-one (allo-pregnanolone); a neurosteroid and positive modulator of the GABAR), which is released during stress, although the effect of the steroid is polarity-dependent, such that it increases inward current, but decreases outward current, at α4β2δ GABAR. Expression of α4β2δ GABAR in CA1 hippocampus is also tightly regulated by fluctuating levels of neurosteroids, as seen at the onset of puberty. Declining levels of inhibition resulting from the decrease in THP at puberty are compensated for by an increase in α4βδ GABAR along the apical dendrites of CA1 hippocampal pyramidal cells, which reduces neuronal excitability by decreasing the input resistance. However, excessive decrease of neuronal function is averted when THP levels rise, as would occur during stress, because this steroid decreases the outward GABAergic tonic current via inhibition of α4β2δ GABAR, thereby restoring measures of neuronal excitability to pre-pubertal levels. Thus the homoeostatic regulation of α4βδ GABAR expression plays an important role in maintaining ambient levels of neuronal excitability at puberty.
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Koh, Ingrid Y. Y., W. Brent Lindquist, Karen Zito, Esther A. Nimchinsky, and Karel Svoboda. "An Image Analysis Algorithm for Dendritic Spines." Neural Computation 14, no. 6 (June 1, 2002): 1283–310. http://dx.doi.org/10.1162/089976602753712945.
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The structure of neuronal dendrites and their spines underlie the connectivity of neural networks. Dendrites, spines, and their dynamics are shaped by genetic programs as well as sensory experience. Dendritic structures and dynamics may therefore be important predictors of the function of neural networks. Based on new imaging approaches and increases in the speed of computation, it has become possible to acquire large sets of high-resolution optical micrographs of neuron structure at length scales small enough to resolve spines. This advance in data acquisition has not been accompanied by comparable advances in data analysis techniques; the analysis of dendritic and spine morphology is still accomplished largely manually. In addition to being extremely time intensive, manual analysis also introduces systematic and hard-to-characterize biases. We present a geometric approach for automatically detecting and quantifying the three-dimensional structure of dendritic spines from stacks of image data acquired using laser scanning microscopy. We present results on the measurement of dendritic spine length, volume, density, and shape classification for both static and timelapse images of dendrites of hippocampal pyramidal neurons. For spine length and density, the automated measurements in static images are compared with manual measurements. Comparisons are also made between automated and manual spine length measurements for a time-series data set. The algorithm performs well compared to a human analyzer, especially on time-series data. Automated analysis of dendritic spine morphology will enable objective analysis of large morphological data sets. The approaches presented here are generalizable to other aspects of neuronal morphology.
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Tyrtyshnaia, Anna, Anatoly Bondar, Sophia Konovalova, and Igor Manzhulo. "Synaptamide Improves Cognitive Functions and Neuronal Plasticity in Neuropathic Pain." International Journal of Molecular Sciences 22, no. 23 (November 26, 2021): 12779. http://dx.doi.org/10.3390/ijms222312779.
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Neuropathic pain arises from damage or dysfunction of the peripheral or central nervous system and manifests itself in a wide variety of sensory symptoms and cognitive disorders. Many studies demonstrate the role of neuropathic pain-induced neuroinflammation in behavioral disorders. For effective neuropathic pain treatment, an integrative approach is required, which simultaneously affects several links of pathogenesis. One promising candidate for this role is synaptamide (N-docosahexaenoylethanolamine), which is an endogenous metabolite of docosahexaenoic acid. In this study, we investigated the activity of synaptamide on mice behavior and hippocampal plasticity in neuropathic pain induced by spared nerve injury (SNI). We found a beneficial effect of synaptamide on the thermal allodynia and mechanical hyperalgesia dynamics. Synaptamide prevented working and long-term memory impairment. These results are probably based on the supportive effect of synaptamide on SNI-impaired hippocampal plasticity. Nerve ligation caused microglia activation predominantly in the contralateral hippocampus, while synaptamide inhibited this effect. The treatment reversed dendritic tree degeneration, dendritic spines density reduction on CA1-pyramidal neurons, neurogenesis deterioration, and hippocampal long-term potentiation (LTP) impairment. In addition, synaptamide inhibits changes in the glutamatergic receptor expression. Thus, synaptamide has a beneficial effect on hippocampal functioning, including synaptic plasticity and hippocampus-dependent cognitive processes in neuropathic pain.
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Lee, Min Soo, Seung Bum Yang, and Jun Ho Heo. "Application of Thallium Autometallography for Observation of Changes in Excitability of Rodent Brain following Acute Carbon Monoxide Intoxication." Journal of The Korean Society of Clinical Toxicology 17, no. 2 (December 31, 2019): 66–78. http://dx.doi.org/10.22537/jksct.2019.17.2.66.
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Purpose: Thallium (TI+) autometallography is often used for the imaging of neuronal metabolic activity in the rodent brain under various pathophysiologic conditions. The purpose of this study was to apply a thallium autometallographic technique to observe changes in neuronal activity in the forebrain of rats following acute carbon monoxide (CO) intoxication. Methods: In order to induce acute CO intoxication, adult Sprague-Dawley rats were exposed to 1100 ppm of CO for 40 minutes, followed by 3000 ppm of CO for 20 minutes. Animals were sacrificed at 30 minutes and 5 days after induction of acute CO intoxication for thallium autometallography. Immunohistochemical staining and toluidine blue staining were performed to observe cellular damage in the forebrain following intoxication. Results: Acute CO intoxication resulted in significant reduction of TI+ uptake in major forebrain structures, including the cortex, hippocampus, thalamus, and striatum. In the cortex and hippocampal CA1 area, marked reduction of TI+ uptake was observed in the cell bodies and dendrites of pyramidal neurons at 30 minutes following acute CO intoxication. There was also strong uptake of TI+ in astrocytes in the hippocampal CA3 area following acute CO intoxication. However, there were no significant histological findings of cell death and no reduction of NeuN (+) neuronal populations in the cortex and hippocampus at 5 days after acute CO intoxication. Conclusion: The results of this study suggest that thallium autometallography can be a new and useful technique for imaging functional changes in neural activity of the forebrain structure following mild to moderate CO intoxication.
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Lee, Min Soo, Seung Bum Yang, and Jun Ho Heo. "Application of Thallium Autometallography for Observation of Changes in Excitability of Rodent Brain following Acute Carbon Monoxide Intoxication." Journal of The Korean Society of Clinical Toxicology 17, no. 2 (December 31, 2019): 66–78. http://dx.doi.org/10.22537/jksct.17.2.66.
Full textAbstract:
Purpose: Thallium (TI+) autometallography is often used for the imaging of neuronal metabolic activity in the rodent brain under various pathophysiologic conditions. The purpose of this study was to apply a thallium autometallographic technique to observe changes in neuronal activity in the forebrain of rats following acute carbon monoxide (CO) intoxication. Methods: In order to induce acute CO intoxication, adult Sprague-Dawley rats were exposed to 1100 ppm of CO for 40 minutes, followed by 3000 ppm of CO for 20 minutes. Animals were sacrificed at 30 minutes and 5 days after induction of acute CO intoxication for thallium autometallography. Immunohistochemical staining and toluidine blue staining were performed to observe cellular damage in the forebrain following intoxication. Results: Acute CO intoxication resulted in significant reduction of TI+ uptake in major forebrain structures, including the cortex, hippocampus, thalamus, and striatum. In the cortex and hippocampal CA1 area, marked reduction of TI+ uptake was observed in the cell bodies and dendrites of pyramidal neurons at 30 minutes following acute CO intoxication. There was also strong uptake of TI+ in astrocytes in the hippocampal CA3 area following acute CO intoxication. However, there were no significant histological findings of cell death and no reduction of NeuN (+) neuronal populations in the cortex and hippocampus at 5 days after acute CO intoxication. Conclusion: The results of this study suggest that thallium autometallography can be a new and useful technique for imaging functional changes in neural activity of the forebrain structure following mild to moderate CO intoxication.
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Zhuravleva, Z. N. "Ultrastructural Signs of Regenerative-Degenerative Processes in Long-Term Dentate Fascia Grafts." Journal of Neural Transplantation and Plasticity 5, no. 3 (1994): 183–97. http://dx.doi.org/10.1155/np.1994.183.
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An ultrastructural investigation of embryonic (E20) dentate fascia grafts transplanted into an acute cavity in the somatosensory neocortex of adult rats revealed a continuous dynamic state of the tissue nine months postgrafting. The grafts consisted mainly of typical granular cells with some admixture of hippocampal pyramidal neurons and polymorph hilar cells with a normal, mature ultrastructure. Many features of the transplanted tissue suggested continuing development and growth. Dendritic branches with growth tips, axonal growth cones, synaptic boutons with growth vesicles, immature myelin sheaths and myelin-producing cells were observed. In contrast, ultrastructural signs of degeneration were present in some axons, and, less often, in dendrites. These processes, as well as some of the terminal synapses, contained various amounts of lysosomes and lipofuscine granules. In many such terminals the signs of degenerative change were combined with the presence of multiple mitochondria, polymorph vesicles and tubular reticulum, indicating simultaneous reparative processes. It is suggested that continuous recycling of neuronal processes occurs in longterm dentate grafts. This morphological instability nay depend on the paucity of synaptic targets within the dentate tissue transplanted with a minimal quantity of hippocampal pyramidal cells and on the limitation of the afferent input. However, the observed features of the grafted dentate tissue are not qualitatively different from those observed in normal dentate with its protracted development and active compensatory reorganization.
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Sakalar, Ece, Thomas Klausberger, and Bálint Lasztóczi. "Neurogliaform cells dynamically decouple neuronal synchrony between brain areas." Science 377, no. 6603 (July 15, 2022): 324–28. http://dx.doi.org/10.1126/science.abo3355.
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Effective communication across brain areas requires distributed neuronal networks to dynamically synchronize or decouple their ongoing activity. GABA ergic interneurons lock ensembles to network oscillations, but there remain questions regarding how synchrony is actively disengaged to allow for new communication partners. We recorded the activity of identified interneurons in the CA1 hippocampus of awake mice. Neurogliaform cells (NGFCs)—which provide GABA ergic inhibition to distal dendrites of pyramidal cells—strongly coupled their firing to those gamma oscillations synchronizing local networks with cortical inputs. Rather than strengthening such synchrony, action potentials of NGFCs decoupled pyramidal cell activity from cortical gamma oscillations but did not reduce their firing nor affect local oscillations. Thus, NGFCs regulate information transfer by temporarily disengaging the synchrony without decreasing the activity of communicating networks.
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Canals, S., I. Makarova, L. López-Aguado, C. Largo, J. M. Ibarz, and O. Herreras. "Longitudinal Depolarization Gradients Along the Somatodendritic Axis of CA1 Pyramidal Cells: A Novel Feature of Spreading Depression." Journal of Neurophysiology 94, no. 2 (August 2005): 943–51. http://dx.doi.org/10.1152/jn.01145.2004.
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We studied the subcellular correlates of spreading depression (SD) in the CA1 rat hippocampus by combining intrasomatic and intradendritic recordings of pyramidal cells with extracellular DC and evoked field and unitary activity. The results demonstrate that during SD only specific parts of the dendritic membranes are deeply depolarized and electrically shunted. Somatic impalements yielded near-zero membrane potential ( Vm) and maximum decrease of input resistance ( Rin) whether the accompanying extracellular negative potential ( Vo) moved along the basal, the apical or both dendritic arbors. However, apical intradendritic recordings showed a different course of local Vm that is hardly detected from the soma. A decreasing depolarization gradient was observed from the edge of SD-affected fully depolarized subcellular regions toward distal dendrites. Within apical dendrites, the depolarizing front moved toward and stopped at proximal dendrites during the time course of SD so that distal dendrites had repolarized in part or in full by the end of the wave. The drop of local Rin was initially maximal at any somatodendritic loci and also recovered partially before the end of SD. This recovery was stronger and faster in far dendrites and is best explained by a wave-like somatopetal closure of membrane conductances. Cell subregions far from SD-affected membranes remain electrically excitable and show evoked unitary and field activity. We propose that neuronal depolarization during SD is caused by current flow through extended but discrete patches of shunted membranes driven by uneven longitudinal depolarization.
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Tyrtyshnaia, Anna A., Igor V. Manzhulo, Sophia P. Konovalova, and Anna A. Zagliadkina. "Neuropathic Pain Causes a Decrease in the Dendritic Tree Complexity of Hippocampal CA3 Pyramidal Neurons." Cells Tissues Organs 208, no. 3-4 (2019): 89–100. http://dx.doi.org/10.1159/000506812.
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The International Pain Association defines neuropathic pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” Recent studies show that chronic neuropathic pain causes both morphological and functional changes within brain structures. Due to the impact of supraspinal centers on pain signal processing, patients with chronic pain often suffer from depression, anxiety, memory impairment, and learning disabilities. Changes in hippocampal neuronal and glial plasticity can play a substantial role in the development of these symptoms. Given the special role of the CA3 hippocampal area in chronic stress reactions, we suggested that this region may undergo significant morphological changes as a result of persistent pain. Since the CA3 area is involved in the implementation of hippocampus-dependent memory, changes in the neuronal morphology can cause cognitive impairment observed in chronic neuropathic pain. This study aimed to elucidate the structural and plastic changes within the hippocampus associated with dendritic tree atrophy of CA3 pyramidal neurons in mice with chronic sciatic nerve constriction. Behavioral testing revealed impaired working and long-term memory in mice with a chronic constriction injury. Using the Golgi-Cox method, we revealed a decrease in the number of branches and dendritic length of CA3 pyramidal neurons. The dendritic spine number was decreased, predominantly due to a reduction in mushroom spines. An immunohistochemical study showed changes in astro- and microglial activity, which could affect the morphology of neurons both directly and indirectly via the regulation of neurotrophic factor synthesis. Using ELISA, we found a decrease in brain-derived neurotrophic factor production and an increase in neurotrophin-3 production. Morphological and biochemical changes in the CA3 area are accompanied by impaired working and long-term memory of animals. Thus, we can conclude that morphological and biochemical changes within the CA3 hippocampal area may underlie the cognitive impairment in neuropathic pain.
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Narayanan, Rishikesh, Anusha Narayan, and Sumantra Chattarji. "A Probabilistic Framework for Region-Specific Remodeling of Dendrites in Three-Dimensional Neuronal Reconstructions." Neural Computation 17, no. 1 (January 1, 2005): 75–96. http://dx.doi.org/10.1162/0899766052530811.
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Dendritic arborization is an important determinant of single-neuron function as well as the circuitry among neurons. Dendritic trees undergo remodeling during development, aging, and many pathological conditions, with many of the morphological changes being confined to certain regions of the dendritic tree. In order to analyze the functional consequences of such region-specific dendritic remodeling, it is essential to develop techniques that can systematically manipulate three-dimensional reconstructions of neurons. Hence, in this study, we develop an algorithm that uses statistics from precise morphometric analyses to systematically remodel neuronal reconstructions. We use the distribution function of the ratio of two normal distributed random variables to specify the probabilities of remodeling along various regions of the dendritic arborization. We then use these probabilities to drive an iterative algorithm for manipulating the dendritic tree in a region-specific manner. As a test, we apply this framework to a well-characterized example of dendritic remodeling: stress-induced dendritic atrophy in hippocampal CA3 pyramidal cells. We show that our pruning algorithm is capable of eliciting atrophy that matches biological data from rodent models of chronic stress.
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Prakash, Chandra, Shyam Sunder Rabidas, Jyoti Tyagi, and Deepak Sharma. "Dehydroepiandrosterone Attenuates Astroglial Activation, Neuronal Loss and Dendritic Degeneration in Iron-Induced Post-Traumatic Epilepsy." Brain Sciences 13, no. 4 (March 27, 2023): 563. http://dx.doi.org/10.3390/brainsci13040563.
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Iron-induced experimental epilepsy in rodents reproduces features of post-traumatic epilepsy (PTE) in humans. The neural network of the brain seems to be highly affected during the course of epileptogenesis and determines the occurrence of sudden and recurrent seizures. The aim of the current study was to evaluate astroglial and neuronal response as well as dendritic arborization, and the spine density of pyramidal neurons in the cortex and hippocampus of epileptic rats. We also evaluated the effect of exogenous administration of a neuroactive steroid, dehydroepiandrosterone (DHEA), in epileptic rats. To induce epilepsy, male Wistar rats were given an intracortical injection of 100 mM solution (5 µL) of iron chloride (FeCl3). After 20 days, DHEA was administered intraperitoneally for 21 consecutive days. Results showed epileptic seizures and hippocampal Mossy Fibers (MFs) sprouting in epileptic rats, while DHEA treatment significantly reduced the MFs’ sprouting. Astroglial activation and neuronal loss were subdued in rats that received DHEA compared to epileptic rats. Dendritic arborization and spine density of pyramidal neurons was diminished in epileptic rats, while DHEA treatment partially restored their normal morphology in the cortex and hippocampus regions of the brain. Overall, these findings suggest that DHEA’s antiepileptic effects may contribute to alleviating astroglial activation and neuronal loss along with enhancing dendritic arborization and spine density in PTE.
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Trivino-Paredes, J. S., P. C. Nahirney, C. Pinar, P. Grandes, and B. R. Christie. "Acute slice preparation for electrophysiology increases spine numbers equivalently in the male and female juvenile hippocampus: a DiI labeling study." Journal of Neurophysiology 122, no. 3 (September 1, 2019): 958–69. http://dx.doi.org/10.1152/jn.00332.2019.
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Hippocampal slices are widely used for in vitro electrophysiological experiments to study underlying mechanisms for synaptic transmission and plasticity, and there is a growing appreciation for sex differences in synaptic plasticity. To date, several studies have shown that the process of making slices from male animals can induce synaptogenesis in cornu ammonis area 1 (CA1) pyramidal cells, but there is a paucity of data for females and other brain regions. In the current study we use microcrystals of the lipophilic carbocyanine dye DiI (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate) to stain individual neurons in the CA1 and dentate gyrus (DG) hippocampal subfields of postnatal day 21 male and female rats. We show that the preparation of sections for electrophysiology produces significant increases in spines in sections obtained from females, similar to that observed in males. We also show that the procedures used for in vitro electrophysiology also result in significant spine increases in the DG and CA1 subfields. These results demonstrate the utility of this refined DiI procedure for staining neuronal dendrites and spines. They also show, for the first time, that in vitro electrophysiology slice preparations enhance spine numbers on hippocampal cells equivalently in both juvenile females and males. NEW & NOTEWORTHY This study introduces a new DiI technique that elucidates differences in spine numbers in juvenile female and male hippocampus, and shows that slice preparations for hippocampal electrophysiology in vitro may mask these differences.
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Ambrogini, Patrizia, Davide Lattanzi, Marica Pagliarini, Michael Di Palma, Stefano Sartini, Riccardo Cuppini, Kjell Fuxe, and Dasiel Oscar Borroto-Escuela. "5HT1AR-FGFR1 Heteroreceptor Complexes Differently Modulate GIRK Currents in the Dorsal Hippocampus and the Dorsal Raphe Serotonin Nucleus of Control Rats and of a Genetic Rat Model of Depression." International Journal of Molecular Sciences 24, no. 8 (April 18, 2023): 7467. http://dx.doi.org/10.3390/ijms24087467.
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The midbrain raphe serotonin (5HT) neurons provide the main ascending serotonergic projection to the forebrain, including hippocampus, which has a role in the pathophysiology of depressive disorder. Serotonin 5HT1A receptor (R) activation at the soma-dendritic level of serotonergic raphe neurons and glutamatergic hippocampal pyramidal neurons leads to a decrease in neuronal firing by activation of G protein-coupled inwardly-rectifying potassium (GIRK) channels. In this raphe-hippocampal serotonin neuron system, the existence of 5HT1AR-FGFR1 heteroreceptor complexes has been proven, but the functional receptor–receptor interactions in the heterocomplexes have only been investigated in CA1 pyramidal neurons of control Sprague Dawley (SD) rats. In the current study, considering the impact of the receptor interplay in developing new antidepressant drugs, the effects of 5HT1AR-FGFR1 complex activation were investigated in hippocampal pyramidal neurons and in midbrain dorsal raphe serotonergic neurons of SD rats and of a genetic rat model of depression (the Flinders Sensitive Line (FSL) rats of SD origin) using an electrophysiological approach. The results showed that in the raphe-hippocampal 5HT system of SD rats, 5HT1AR-FGFR1 heteroreceptor activation by specific agonists reduced the ability of the 5HT1AR protomer to open the GIRK channels through the allosteric inhibitory interplay produced by the activation of the FGFR1 protomer, leading to increased neuronal firing. On the contrary, in FSL rats, FGFR1 agonist-induced inhibitory allosteric action at the 5HT1AR protomer was not able to induce this effect on GIRK channels, except in CA2 neurons where we demonstrated that the functional receptor–receptor interaction is needed for producing the effect on GIRK. In keeping with this evidence, hippocampal plasticity, evaluated as long-term potentiation induction ability in the CA1 field, was impaired by 5HT1AR activation both in SD and in FSL rats, which did not develop after combined 5HT1AR-FGFR1 heterocomplex activation in SD rats. It is therefore proposed that in the genetic FSL model of depression, there is a significant reduction in the allosteric inhibition exerted by the FGFR1 protomer on the 5HT1A protomer-mediated opening of the GIRK channels in the 5HT1AR-FGFR1 heterocomplex located in the raphe-hippocampal serotonin system. This may result in an enhanced inhibition of the dorsal raphe 5HT nerve cell and glutamatergic hippocampal CA1 pyramidal nerve cell firing, which we propose may have a role in depression.
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McEwen, B. S., A. M. Magarinos, and L. P. Reagan. "Structural plasticity and tianeptine: cellular and molecular targets." European Psychiatry 17, S3 (July 2002): 318s—330s. http://dx.doi.org/10.1016/s0924-9338(02)00650-8.
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SummaryThe hippocampal formation, a structure involved in declarative, spatial and contextual memory, undergoes atrophy in depressive illness along with impairment in cognitive function. Animal model studies have shown that the hippocampus is a particularly sensitive and vulnerable brain region that responds to stress and stress hormones. Studies on models of stress and glucocorticoid actions reveal that the hippocampus shows a considerable degree of structural plasticity in the adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and repeated stress causes remodeling of dendrites in the CA3 region, a region that is particularly important in memory processing. Both forms of structural remodeling of the hippocampus are mediated by adrenal steroids working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, head trauma, and ischemia, and alterations of calcium homeostasis that accompany age-related cognitive impairment. Tianeptine (tianeptine) is an effective antidepressant that prevents and even reverses the actions of stress and glucocorticoids on dendritic remodeling in an animal model of chronic stress. Multiple neurotransmitter systems contribute to dendritic remodeling, including EAA, serotonin, and gamma-aminobutyric acid (GABA), working synergistically with glucocorticoids. This review summarizes findings on neurochemical targets of adrenal steroid actions that may explain their role in the remodeling process. In studying these actions, we hope to better understand the molecular and cellular targets of action of tianeptine in relation to its role in influencing structural plasticity of the hippocampus.
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Sancho-Balsells, Anna, Sara Borràs-Pernas, Verónica Brito, Jordi Alberch, Jean-Antoine Girault, and Albert Giralt. "Cognitive and Emotional Symptoms Induced by Chronic Stress Are Regulated by EGR1 in a Subpopulation of Hippocampal Pyramidal Neurons." International Journal of Molecular Sciences 24, no. 4 (February 14, 2023): 3833. http://dx.doi.org/10.3390/ijms24043833.
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Chronic stress is a core risk factor for developing a myriad of neurological disorders, including major depression. The chronicity of such stress can lead to adaptive responses or, on the contrary, to psychological maladaptation. The hippocampus is one of the most affected brain regions displaying functional changes in chronic stress. Egr1, a transcription factor involved in synaptic plasticity, is a key molecule regulating hippocampal function, but its role in stress-induced sequels has been poorly addressed. Emotional and cognitive symptoms were induced in mice by using the chronic unpredictable mild stress (CUMS) protocol. We used inducible double-mutant Egr1-CreERT2 x R26RCE mice to map the formation of Egr1-dependent activated cells. Results show that short- (2 days) or long-term (28 days) stress protocols in mice induce activation or deactivation, respectively, of hippocampal CA1 neural ensembles in an Egr1-activity-dependent fashion, together with an associated dendritic spine pathology. In-depth characterization of these neural ensembles revealed a deep-to-superficial switch in terms of Egr1-dependent activation of CA1 pyramidal neurons. To specifically manipulate deep and superficial pyramidal neurons of the hippocampus, we then used Chrna7-Cre (to express Cre in deep neurons) and Calb1-Cre mice (to express Cre in superficial neurons). We found that specific manipulation of superficial but not deep pyramidal neurons of the CA1 resulted in the amelioration of depressive-like behaviors and the restoration of cognitive impairments induced by chronic stress. In summary, Egr1 might be a core molecule driving the activation/deactivation of hippocampal neuronal subpopulations underlying stress-induced alterations involving emotional and cognitive sequels.
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Chen, Chu, and Nicolas G. Bazan. "Endogenous PGE2 Regulates Membrane Excitability and Synaptic Transmission in Hippocampal CA1 Pyramidal Neurons." Journal of Neurophysiology 93, no. 2 (February 2005): 929–41. http://dx.doi.org/10.1152/jn.00696.2004.
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The significance of cyclooxygenases (COXs), the rate-limiting enzymes that convert arachidonic acid (AA) to prostaglandins (PGs) in the brain, is unclear, although they have been implicated in inflammatory responses and in some neurological disorders such as epilepsy and Alzheimer's disease. Recent evidence that COX-2, which is expressed in postsynaptic dendritic spines, regulates PGE2 signaling in activity-dependent long-term synaptic plasticity at hippocampal perforant path-dentate granule cell synapses, suggests an important role of the COX-2–generated PGE2 in synaptic signaling. However, little is known of how endogenous PGE2 regulates neuronal signaling. Here we showed that endogenous PGE2 selectively regulates fundamental membrane and synaptic properties in the hippocampus. Somatic and dendritic membrane excitability was significantly reduced when endogenous PGE2 was eliminated with a selective COX-2 inhibitor in hippocampal CA1 pyramidal neurons in slices. Exogenous application of PGE2 produced significant increases in frequency of firing, excitatory postsynaptic potentials (EPSP) amplitude, and temporal summation in slices treated with the COX-2 inhibitor. The PGE2-induced increase in membrane excitability seemed to result from its inhibition of the potassium currents, which in turn, boosted dendritic Ca2+ influx during dendritic-depolarizing current injections. In addition, the PGE2-induced enhancement of EPSPs was blocked by eliminating both PKA and PKC activities. These findings indicate that endogenous PGE2 dynamically regulates membrane excitability, synaptic transmission, and plasticity and that the PGE2-induced synaptic modulation is mediated via cAMP-PKA and PKC pathways in rat hippocampal CA1 pyramidal neurons.
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Park, Hae Jeong, Ira Rajbhandari, Han Soo Yang, Soojung Lee, Delia Cucoranu, Deborah S. Cooper, Janet D. Klein, Jeff M. Sands, and Inyeong Choi. "Neuronal expression of sodium/bicarbonate cotransporter NBCn1 (SLC4A7) and its response to chronic metabolic acidosis." American Journal of Physiology-Cell Physiology 298, no. 5 (May 2010): C1018—C1028. http://dx.doi.org/10.1152/ajpcell.00492.2009.
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The sodium-bicarbonate cotransporter NBCn1 (SLC4A7) is an acid-base transporter that normally moves Na+ and HCO3− into the cell. This membrane protein is sensitive to cellular and systemic pH changes. We examined NBCn1 expression and localization in the brain and its response to chronic metabolic acidosis. Two new NBCn1 antibodies were generated by immunizing a rabbit and a guinea pig. The antibodies stained neurons in a variety of rat brain regions, including hippocampal pyramidal neurons, dentate gyrus granular neurons, posterior cortical neurons, and cerebellar Purkinje neurons. Choroid plexus epithelia were also stained. Double immunofluorescence labeling showed that NBCn1 and the postsynaptic density protein PSD-95 were found in the same hippocampal CA3 neurons and partially colocalized in dendrites. PSD-95 was pulled down from rat brain lysates with the GST/NBCn1 fusion protein and was also coimmunoprecipitated with NBCn1. Chronic metabolic acidosis was induced by feeding rats with normal chow or 0.4 M HCl-containing chow for 7 days. Real-time PCR and immunoblot showed upregulation of NBCn1 mRNA and protein in the hippocampus of acidotic rats. NBCn1 immunostaining was enhanced in CA3 neurons, posterior cortical neurons, and cerebellar granular cells. Intraperitoneal administration of N-methyl-d-aspartate caused neuronal death determined by caspase-3 activity, and this effect was more severe in acidotic rats. Administering N-methyl-d-aspartate also inhibited NBCn1 upregulation in acidotic rats. We conclude that NBCn1 in neurons is upregulated by chronic acid loads, and this upregulation is associated with glutamate excitotoxicity.
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Clemens, Ann M., and Daniel Johnston. "Age- and location-dependent differences in store depletion-induced h-channel plasticity in hippocampal pyramidal neurons." Journal of Neurophysiology 111, no. 6 (March 15, 2014): 1369–82. http://dx.doi.org/10.1152/jn.00839.2013.
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Disruptions of endoplasmic reticulum (ER) Ca2+ homeostasis are heavily linked to neuronal pathology. Depletion of ER Ca2+ stores can result in cellular dysfunction and potentially cell death, although adaptive processes exist to aid in survival. We examined the age and region dependence of one postulated, adaptive response to ER store-depletion (SD), hyperpolarization-activated cation-nonspecific ( h)-channel plasticity in neurons of the dorsal and ventral hippocampus (DHC and VHC, respectively) from adolescent and adult rats. With the use of whole-cell patch-clamp recordings from the soma and dendrites of CA1 pyramidal neurons, we observed a change in h-sensitive measurements in response to SD, induced by treatment with cyclopiazonic acid, a sarcoplasmic reticulum/ER Ca2+-ATPase blocker. We found that whereas DHC and VHC neurons in adolescent animals respond to SD with a perisomatic expression of SD h plasticity, adult animals express SD h plasticity with a dendritic and somatodendritic locus of plasticity in DHC and VHC neurons, respectively. Furthermore, SD h plasticity in adults was dependent on membrane potential and on the activation of L-type voltage-gated Ca2+ channels. These results suggest that cellular responses to the impairment of ER function, or ER stress, are dependent on brain region and age and that the differential expression of SD h plasticity could provide a neural basis for region- and age-dependent disease vulnerabilities.
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Ruiter, Marvin, Lotte J. Herstel, and Corette J. Wierenga. "Reduction of Dendritic Inhibition in CA1 Pyramidal Neurons in Amyloidosis Models of Early Alzheimer’s Disease." Journal of Alzheimer's Disease 78, no. 3 (November 24, 2020): 951–64. http://dx.doi.org/10.3233/jad-200527.
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Background: In an early stage of Alzheimer’s disease (AD), before the formation of amyloid plaques, neuronal network hyperactivity has been reported in both patients and animal models. This suggests an underlying disturbance of the balance between excitation and inhibition. Several studies have highlighted the role of somatic inhibition in early AD, while less is known about dendritic inhibition. Objective: In this study we investigated how inhibitory synaptic currents are affected by elevated Aβ levels. Methods: We performed whole-cell patch clamp recordings of CA1 pyramidal neurons in organotypic hippocampal slice cultures after treatment with Aβ-oligomers and in hippocampal brain slices from AppNL-F-G mice (APP-KI). Results: We found a reduction of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in organotypic slices after 24 h Aβ treatment. sIPSCs with slow rise times were reduced, suggesting a specific loss of dendritic inhibitory inputs. As miniature IPSCs and synaptic density were unaffected, these results suggest a decrease in activity-dependent transmission after Aβ treatment. We observed a similar, although weaker, reduction in sIPSCs in CA1 pyramidal neurons from APP-KI mice compared to control. When separated by sex, the strongest reduction in sIPSC frequency was found in slices from male APP-KI mice. Consistent with hyperexcitability in pyramidal cells, dendritically targeting interneurons received slightly more excitatory input. GABAergic action potentials had faster kinetics in APP-KI slices. Conclusion: Our results show that Aβ affects dendritic inhibition via impaired action potential driven release, possibly due to altered kinetics of GABAergic action potentials. Reduced dendritic inhibition may contribute to neuronal hyperactivity in early AD.
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Castello-Waldow, Tim P., Ghabiba Weston, Alessandro F. Ulivi, Alireza Chenani, Yonatan Loewenstein, Alon Chen, and Alessio Attardo. "Hippocampal neurons with stable excitatory connectivity become part of neuronal representations." PLOS Biology 18, no. 11 (November 3, 2020): e3000928. http://dx.doi.org/10.1371/journal.pbio.3000928.
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Experiences are represented in the brain by patterns of neuronal activity. Ensembles of neurons representing experience undergo activity-dependent plasticity and are important for learning and recall. They are thus considered cellular engrams of memory. Yet, the cellular events that bias neurons to become part of a neuronal representation are largely unknown. In rodents, turnover of structural connectivity has been proposed to underlie the turnover of neuronal representations and also to be a cellular mechanism defining the time duration for which memories are stored in the hippocampus. If these hypotheses are true, structural dynamics of connectivity should be involved in the formation of neuronal representations and concurrently important for learning and recall. To tackle these questions, we used deep-brain 2-photon (2P) time-lapse imaging in transgenic mice in which neurons expressing the Immediate Early Gene (IEG) Arc (activity-regulated cytoskeleton-associated protein) could be permanently labeled during a specific time window. This enabled us to investigate the dynamics of excitatory synaptic connectivity—using dendritic spines as proxies—of hippocampal CA1 (cornu ammonis 1) pyramidal neurons (PNs) becoming part of neuronal representations exploiting Arc as an indicator of being part of neuronal representations. We discovered that neurons that will prospectively express Arc have slower turnover of synaptic connectivity, thus suggesting that synaptic stability prior to experience can bias neurons to become part of representations or possibly engrams. We also found a negative correlation between stability of structural synaptic connectivity and the ability to recall features of a hippocampal-dependent memory, which suggests that faster structural turnover in hippocampal CA1 might be functional for memory.
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O'Beirne, M., N. Gurevich, and P. L. Carlen. "Pentobarbital inhibits hippocampal neurons by increasing potassium conductance." Canadian Journal of Physiology and Pharmacology 65, no. 1 (January 1, 1987): 36–41. http://dx.doi.org/10.1139/y87-007.
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The effects of sodium pentobarbital were studied using intracellular recordings from CA1 and CA3 pyramidal cells in slices of guinea pig hippocampus. Drugs were applied either by perfusion or by pressure ejection at concentrations of 10−6, 10−5, and 10−4 M. Pentobarbital at all concentrations caused neuronal hyperpolarization, decreased spontaneous activity, and sometimes decreased input resistance. Hyperpolarization also occurred in zero calcium perfusate or with tetrodotoxin in the perfusate. The postspike train long-lasting afterhyperpolarization, which is an intrinsic calcium-mediated potassium conductance, was increased at all doses. γ-Aminobutyric acid induced depolarizing dendritic responses were augmented only at 10−4 M pentobarbital. It is proposed that one of the important mechanisms of pentobarbital neuronal inhibition, particularly at lower doses, is an increase in potassium conductance.
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D'Apuzzo, Massimo, Georgia Mandolesi, Gerald Reis, and Erin M. Schuman. "Abundant GFP Expression and LTP in Hippocampal Acute Slices by In Vivo Injection of Sindbis Virus." Journal of Neurophysiology 86, no. 2 (August 1, 2001): 1037–42. http://dx.doi.org/10.1152/jn.2001.86.2.1037.
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Virus-mediated gene transfer into neurons is a powerful tool for the analysis of neuronal structure and function. Recombinant sindbis virus has been previously used to study protein function in hippocampal neuron cultures as well as in hippocampal organotypic slice cultures. Nevertheless, some concern still exists about the physiological relevance of these cultured preparations. Acute hippocampal slices are a widely used preparation for the study of synaptic transmission, but currently recombinant gene delivery is usually achieved only through time-consuming transgenic techniques. In this study, we show that a subregion of the CA1 area in acute hippocampal slices can be specifically altered to express a gene of interest. A sindbis virus vector carrying an enhanced green fluorescent protein (EGFP) reporter was injected in vivo into the hippocampus of adult rats. After 18 h, rats were killed, and acute hippocampal slices, infected in the CA1 field, were analyzed morphologically and electrophysiologically. Infected slices showed healthy and stable electrophysiological responses as well as long-term potentiation. In addition, infected pyramidal cells were readily recognized in living slices by two-photon imaging. Specifically, the introduction of an EGFP-Actin fusion protein greatly enhanced the detection of fine processes and dendritic spines. We propose this technique as an efficient tool for studying gene function in adult hippocampal neurons.
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Hodapp, Alexander, Martin E. Kaiser, Christian Thome, Lingjun Ding, Andrei Rozov, Matthias Klumpp, Nikolas Stevens, et al. "Dendritic axon origin enables information gating by perisomatic inhibition in pyramidal neurons." Science 377, no. 6613 (September 23, 2022): 1448–52. http://dx.doi.org/10.1126/science.abj1861.
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Information processing in neuronal networks involves the recruitment of selected neurons into coordinated spatiotemporal activity patterns. This sparse activation results from widespread synaptic inhibition in conjunction with neuron-specific synaptic excitation. We report the selective recruitment of hippocampal pyramidal cells into patterned network activity. During ripple oscillations in awake mice, spiking is much more likely in cells in which the axon originates from a basal dendrite rather than from the soma. High-resolution recordings in vitro and computer modeling indicate that these spikes are elicited by synaptic input to the axon-carrying dendrite and thus escape perisomatic inhibition. Pyramidal cells with somatic axon origin can be activated during ripple oscillations by blocking their somatic inhibition. The recruitment of neurons into active ensembles is thus determined by axonal morphological features.
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Sáray, Sára, Christian A. Rössert, Shailesh Appukuttan, Rosanna Migliore, Paola Vitale, Carmen A. Lupascu, Luca L. Bologna, et al. "HippoUnit: A software tool for the automated testing and systematic comparison of detailed models of hippocampal neurons based on electrophysiological data." PLOS Computational Biology 17, no. 1 (January 29, 2021): e1008114. http://dx.doi.org/10.1371/journal.pcbi.1008114.
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Anatomically and biophysically detailed data-driven neuronal models have become widely used tools for understanding and predicting the behavior and function of neurons. Due to the increasing availability of experimental data from anatomical and electrophysiological measurements as well as the growing number of computational and software tools that enable accurate neuronal modeling, there are now a large number of different models of many cell types available in the literature. These models were usually built to capture a few important or interesting properties of the given neuron type, and it is often unknown how they would behave outside their original context. In addition, there is currently no simple way of quantitatively comparing different models regarding how closely they match specific experimental observations. This limits the evaluation, re-use and further development of the existing models. Further, the development of new models could also be significantly facilitated by the ability to rapidly test the behavior of model candidates against the relevant collection of experimental data. We address these problems for the representative case of the CA1 pyramidal cell of the rat hippocampus by developing an open-source Python test suite, which makes it possible to automatically and systematically test multiple properties of models by making quantitative comparisons between the models and electrophysiological data. The tests cover various aspects of somatic behavior, and signal propagation and integration in apical dendrites. To demonstrate the utility of our approach, we applied our tests to compare the behavior of several different rat hippocampal CA1 pyramidal cell models from the ModelDB database against electrophysiological data available in the literature, and evaluated how well these models match experimental observations in different domains. We also show how we employed the test suite to aid the development of models within the European Human Brain Project (HBP), and describe the integration of the tests into the validation framework developed in the HBP, with the aim of facilitating more reproducible and transparent model building in the neuroscience community.
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Endo, Toshiaki, Etsuko Tarusawa, Takuya Notomi, Katsuyuki Kaneda, Masumi Hirabayashi, Ryuichi Shigemoto, and Tadashi Isa. "Dendritic Ih Ensures High-Fidelity Dendritic Spike Responses of Motion-Sensitive Neurons in Rat Superior Colliculus." Journal of Neurophysiology 99, no. 5 (May 2008): 2066–76. http://dx.doi.org/10.1152/jn.00556.2007.
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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that generate Ih currents are widely distributed in the brain and have been shown to contribute to various neuronal functions. In the present study, we investigated the functions of Ih in the motion-sensitive projection neurons [wide field vertical (WFV) cells] of the superior colliculus, a pivotal visual center for detection of and orientating to salient objects. Combination of whole cell recordings and immunohistochemical investigations suggested that HCN1 channels dominantly contribute to the Ih in WFV cells among HCN isoforms expressed in the superficial superior colliculus and mainly located on their expansive dendritic trees. We found that blocking Ih suppressed the initiation of short- and fixed-latency dendritic spike responses and led instead to long- and fluctuating-latency somatic spike responses to optic fiber stimulations. These results suggest that the dendritic Ih facilitates the dendritic initiation and/or propagation of action potentials and ensures that WFV cells generate spike responses to distal synaptic inputs in a sensitive and robustly time-locked manner, probably by acting as continuous depolarizing drive and fixing dendritic membrane potentials close to the spike threshold. These functions are different from known functions of dendritic Ih revealed in hippocampal and neocortical pyramidal cells, where they spatiotemporally limit the propagations of synaptic inputs along the apical dendrites by reducing dendritic membrane resistance. Thus we have revealed new functional aspects of Ih, and these dendritic properties are likely critical for visual motion processing in these neurons.
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Huguenard, John. "Neurotransmitter Supply and Demand in Epilepsy." Epilepsy Currents 3, no. 2 (March 2003): 61. http://dx.doi.org/10.1111/j.1535-7597.2003.03210.x.
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Block of Glutamate-Glutamine Cycle Between Astrocytes and Neurons Inhibits Epileptiform Activity in Hippocampus Bacci A, Sancini G, Verderio C, Armano C, Pravettoni E, Fesce R, Franceschetti S, Matteoli M J Neurophysiol 2002;88:2302–2310 Recurrent epileptiform activity occurs spontaneously in cultured CNS neurons and in brain slices in which γ-aminobutyric acid (GABA) inhibition has been blocked. We demonstrate here that pharmacologic treatments, resulting in either the block of glutamine production by astrocytes or the inhibition of glutamine uptake by neurons, suppress or markedly decrease the frequency of spontaneous epileptiform discharges both in primary hippocampal cultures and in disinhibited hippocampal slices. These data point to an important role for the neuron-astrocyte metabolic interaction in sustaining episodes of intense rhythmic activity in the CNS, and thereby reveal a new potential target for antiepileptic treatments. A Neuronal Glutamate Transporter Contributes to Neurotransmitter GABA Synthesis and Epilepsy Sepkuty JP, Cohen AS, Eccles C, Rafiq A, Behar K, Ganel R, Coulter DA, Rothstein JD J Neuroscience 2002;22:6372–6379. The predominant neuronal glutamate transporter, EAAC1 (excitatory amino acid carrier-1), is localized to the dendrites and somata of many neurons. Rare presynaptic localization is restricted to γ-aminobutyric acid (GABA) terminals. Because glutamate is a precursor for GABA synthesis, we hypothesized that EAAC1 may play a role in regulating GABA synthesis and thus could cause epilepsy in rats when inactivated. Reduced expression of EAAC1 by antisense treatment led to behavioral abnormalities, including staring-freezing episodes and electrographic (EEG) seizures. Extracellular hippocampal and thalamocortical slice recordings showed excessive excitability in antisense-treated rats. Patch-clamp recordings of miniature inhibitory postsynaptic potentials (mIPSCs) conducted in CA1 pyramidal neurons in slices from EAAC1 antisense-treated animals demonstrated a significant decrease in mIPSC amplitude, indicating decreased tonic inhibition. A 50% loss of hippocampal GABA levels was associated with knockdown of EAAC1, and newly synthesized GABA from extracellular glutamate was significantly impaired by reduction of EAAC1 expression. EAAC1 may participate in normal GABA neurosynthesis and limbic hyperexcitability, whereas epilepsy can result from a disruption of the interaction between EAAC1 and GABA metabolism
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Kucharz, Krzysztof, Tadeusz Wieloch, and Håkan Toresson. "Rapid Fragmentation of the Endoplasmic Reticulum in Cortical Neurons of the Mouse Brain in situ Following Cardiac Arrest." Journal of Cerebral Blood Flow & Metabolism 31, no. 8 (April 6, 2011): 1663–67. http://dx.doi.org/10.1038/jcbfm.2011.37.
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Neuronal endoplasmic reticulum (ER), continuous from soma to dendritic spines, undergoes rapid fragmentation in response to N-methyl-D-aspartate (NMDA) receptor stimulation in hippocampal slices and neuronal primary cultures. Here, we show that ER fragments in the mouse brain following cardiac arrest (CA) induced brain ischemia. The ER structure was assessed in vivo in cortical pyramidal neurons in transgenic mice expressing ER-targeted GFP using two-photon laser scanning microscopy with fluorescence recovery after photobleaching (FRAP). Endoplasmic reticulum fragmentation occurred 1 to 2 minutes after CA and once induced, fragmentation was rapid (< 15 seconds). We propose that acute ER fragmentation may be a protective response against severe ischemic stress.
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Malik, Ruchi, and Sumantra Chattarji. "Enhanced intrinsic excitability and EPSP-spike coupling accompany enriched environment-induced facilitation of LTP in hippocampal CA1 pyramidal neurons." Journal of Neurophysiology 107, no. 5 (March 1, 2012): 1366–78. http://dx.doi.org/10.1152/jn.01009.2011.
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Environmental enrichment (EE) is a well-established paradigm for studying naturally occurring changes in synaptic efficacy in the hippocampus that underlie experience-induced modulation of learning and memory in rodents. Earlier research on the effects of EE on hippocampal plasticity focused on long-term potentiation (LTP). Whereas many of these studies investigated changes in synaptic weight, little is known about potential contributions of neuronal excitability to EE-induced plasticity. Here, using whole-cell recordings in hippocampal slices, we address this gap by analyzing the impact of EE on both synaptic plasticity and intrinsic excitability of hippocampal CA1 pyramidal neurons. Consistent with earlier reports, EE increased contextual fear memory and dendritic spine density on CA1 cells. Furthermore, EE facilitated LTP at Schaffer collateral inputs to CA1 pyramidal neurons. Analysis of the underlying causes for enhanced LTP shows EE to increase the frequency but not amplitude of miniature excitatory postsynaptic currents. However, presynaptic release probability, assayed using paired-pulse ratios and use-dependent block of N-methyl-d-aspartate receptor currents, was not affected. Furthermore, CA1 neurons fired more action potentials (APs) in response to somatic depolarization, as well as during the induction of LTP. EE also reduced spiking threshold and after-hyperpolarization amplitude. Strikingly, this EE-induced increase in excitability caused the same-sized excitatory postsynaptic potential to fire more APs. Together, these findings suggest that EE may enhance the capacity for plasticity in CA1 neurons, not only by strengthening synapses but also by enhancing their efficacy to fire spikes—and the two combine to act as an effective substrate for amplifying LTP.
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Prince, Luke Y., Travis Bacon, Rachel Humphries, Krasimira Tsaneva-Atanasova, Claudia Clopath, and Jack R. Mellor. "Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits." PLOS Computational Biology 17, no. 10 (October 1, 2021): e1009435. http://dx.doi.org/10.1371/journal.pcbi.1009435.
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In the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. The neuromodulators acetylcholine and noradrenaline are separately proposed as saliency signals that dictate memory encoding but it is not known if they represent distinct signals with separate mechanisms. Here, we show experimentally that acetylcholine, and to a lesser extent noradrenaline, suppress feed-forward inhibition and enhance Excitatory–Inhibitory ratio in the mossy fiber pathway but CA3 recurrent network properties are only altered by acetylcholine. We explore the implications of these findings on CA3 ensemble formation using a hierarchy of models. In reconstructions of CA3 pyramidal cells, mossy fiber pathway disinhibition facilitates postsynaptic dendritic depolarization known to be required for synaptic plasticity at CA3-CA3 recurrent synapses. We further show in a spiking neural network model of CA3 how acetylcholine-specific network alterations can drive rapid overlapping ensemble formation. Thus, through these distinct sets of mechanisms, acetylcholine and noradrenaline facilitate the formation of neuronal ensembles in CA3 that encode salient episodic memories in the hippocampus but acetylcholine selectively enhances the density of memory storage.
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Dudek, F. Edward. "Are Altered Excitatory Synapses Found in Neuronal Migration Disorders?" Epilepsy Currents 5, no. 5 (September 2005): 171–73. http://dx.doi.org/10.1111/j.1535-7511.2005.00054.x.
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Physiological and Morphological Characterization of Dentate Granule Cells in the p35 Knock-out Mouse Hippocampus: Evidence for an Epileptic Circuit Patel LS, Wenzel HJ, Schwartzkroin PA J Neurosci 2004;24:9005–9014 There is a high correlation between pediatric epilepsies and neuronal migration disorders. What remains unclear is whether intrinsic features of the individual dysplastic cells give rise to heightened seizure susceptibility, or whether these dysplastic cells contribute to seizure activity by establishing abnormal circuits that alter the balance of inhibition and excitation. Mice lacking a functional p35 gene provide an ideal model in which to address these questions, because these knockout animals not only exhibit aberrant neuronal migration but also demonstrate spontaneous seizures. Extracellular field recordings from hippocampal slices, characterizing the input–output relation in the dentate, revealed little difference between wild-type and knockout mice under both normal and elevated extracellular potassium conditions. However, in the presence of the GABAA antagonist bicuculline, p35 knockout slices, but not wild-type slices, exhibited prolonged depolarizations in response to stimulation of the perforant path. No significant differences were found in the intrinsic properties of dentate granule cells (i.e., input resistance, time constant, action-potential generation) from wild-type versus knockout mice. However, antidromic activation (mossy fiber stimulation) evoked an excitatory synaptic response in more than 65% of granule cells from p35 knockout slices that was never observed in wild-type slices. Ultrastructural analyses identified morphological substrates for this aberrant excitation: recurrent axon collaterals, abnormal basal dendrites, and mossy fiber terminals forming synapses onto the spines of neighboring granule cells. These studies suggest that granule cells in p35 knockout mice contribute to seizure activity by forming an abnormal excitatory feedback circuit. Prolonged NMDA-mediated Synaptic Response, Altered Ifenprodil Sensitivity, and Generation of Epileptiform-like Events in a Malformed Hippocampus of Rats Exposed to Methylazoxymethanol in Utero Calcagnotto ME, Baraban SC J Neurophysiol 2005 [Epub ahead of print] Cortical malformations are often associated with refractory epilepsy and cognitive deficit. Clinical and experimental studies have demonstrated an important role for glutamate-mediated synaptic transmission in these conditions. With whole-cell voltage-clamp techniques, we examined evoked glutamate-mediated excitatory postsynaptic currents (eEPSCs) and responses to exogenously applied glutamate on hippocampal heterotopic cells in an animal model of malformation (i.e., rats exposed to methylazoxymethanol [MAM] in utero). Analysis of eEPSCs revealed that the late N-methyl-D-aspartate (NMDA) receptor–mediated eEPSC component was significantly increased on heterotopic cells compared with age-matched normotopic pyramidal cells. At a holding potential of +40 mV, heterotopic cells also exhibited eEPSCs with a slower decay-time constant. No differences in the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) component of eEPSCs were detected. In 23% of heterotopic pyramidal cells, electrical stimulation evoked prolonged burstlike responses. Focal application of glutamate (10 m M) targeted to different sites near the heterotopia also evoked epileptiform-like bursts on heterotopic cells. Ifenprodil (10 μM), an NR2B subunit antagonist, only slightly reduced the NMDA receptor–mediated component and amplitude of eEPSCs on heterotopic cells (MAM) but significantly decreased the late component and peak amplitude of eEPSCs in normotopic cells (Control). Our data demonstrate a functional alteration in the NMDA-mediated component of excitatory synaptic transmission in heterotopic cells and suggest that this alteration may be attributable, at least in part, to changes in composition and function of the NMDAR subunit. Changes in NMDA-receptor function may directly contribute to the hyperexcitability and cognitive deficits reported in animal models and patients with brain malformations.
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Scott, Courtney A., John P. Rossiter, R. David Andrew, and Alan C. Jackson. "Structural Abnormalities in Neurons Are Sufficient To Explain the Clinical Disease and Fatal Outcome of Experimental Rabies in Yellow Fluorescent Protein-Expressing Transgenic Mice." Journal of Virology 82, no. 1 (October 17, 2007): 513–21. http://dx.doi.org/10.1128/jvi.01677-07.
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ABSTRACT Under natural conditions and in some experimental models, rabies virus infection of the central nervous system causes relatively mild histopathological changes, without prominent evidence of neuronal death despite its lethality. In this study, the effects of rabies virus infection on the structure of neurons were investigated with experimentally infected transgenic mice expressing yellow fluorescent protein (YFP) in neuronal subpopulations. Six-week-old mice were inoculated in the hind-limb footpad with the CVS strain of fixed virus or were mock infected with vehicle (phosphate-buffered saline). Brain regions were subsequently examined by light, epifluorescent, and electron microscopy. In moribund CVS-infected mice, histopathological changes were minimal in paraffin-embedded tissue sections, although mild inflammatory changes were present. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and caspase-3 immunostaining showed only a few apoptotic cells in the cerebral cortex and hippocampus. Silver staining demonstrated the preservation of cytoskeletal integrity in the cerebral cortex. However, fluorescence microscopy revealed marked beading and fragmentation of the dendrites and axons of layer V pyramidal neurons in the cerebral cortex, cerebellar mossy fibers, and axons in brainstem tracts. At an earlier time point, when mice displayed hind-limb paralysis, beading was observed in a few axons in the cerebellar commissure. Toluidine blue-stained resin-embedded sections from moribund YFP-expressing animals revealed vacuoles within the perikarya and proximal dendrites of pyramidal neurons in the cerebral cortex and hippocampus. These vacuoles corresponded with swollen mitochondria under electron microscopy. Vacuolation was also observed ultrastructurally in axons and in presynaptic nerve endings. We conclude that the observed structural changes are sufficient to explain the severe clinical disease with a fatal outcome in this experimental model of rabies.
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Poolos, Nicholas P. "H-Channels and Seizures: Less is More." Epilepsy Currents 5, no. 3 (May 2005): 89–90. http://dx.doi.org/10.1111/j.1535-7511.2005.05302.x.
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Seizure-induced Plasticity of h Channels in Entorhinal Cortical Layer III Pyramidal Neurons Shah MM, Anderson AE, Leung V, Lin X, Johnston D Neuron 2004;44:495–508 The entorhinal cortex (EC) provides the predominant excitatory drive to the hippocampal CA1 and subicular neurons in chronic epilepsy. Discerning the mechanisms underlying signal integration within EC neurons is essential for understanding network excitability alterations involving the hippocampus during epilepsy. Twenty-four hours after a single seizure episode when no behavioral or electrographic seizures occurred, we found enhanced spontaneous activity still present in the rat EC in vivo and in vitro. The increased excitability was accompanied by a profound reduction in Ih in EC layer III neurons and a significant decline in hyperpolarization-activated cation (HCN)1 and HCN2 subunits that encode for h channels. Consequently, dendritic excitability was enhanced, resulting in increased neuronal firing despite hyperpolarized membrane potentials. The loss of Ih and the increased neuronal excitability persisted for 1 week after seizures. Our results suggest that dendritic Ih plays an important role in determining the excitability of EC layer III neurons and their associated neural networks.
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Bracke, Alexander, Grazyna Domanska, Katharina Bracke, Steffen Harzsch, Jens van den Brandt, Barbara Bröker, and Oliver von Bohlen und Halbach. "Obesity Impairs Mobility and Adult Hippocampal Neurogenesis." Journal of Experimental Neuroscience 13 (January 2019): 117906951988358. http://dx.doi.org/10.1177/1179069519883580.
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Currently, it is controversially discussed whether a relationship between obesity and cognition exists. We here analyzed a mouse model of obesity (leptin-deficient mice) to study the effects of obesity on the morphology of the hippocampus (a brain structure involved in mechanisms related to learning and memory) and on behavior. Mice aged 4 to 6 months were analyzed. At this age, the obese mice have nearly double the body weight as controls, but display smaller brains (brain volume is about 10% smaller) as control animals of the same age. Adult hippocampal neurogenesis, a process that is linked to learning and memory, might be disturbed in the obese mice and contribute to the smaller brain volume. Adult hippocampal neurogenesis was examined using specific markers for cell proliferation (phosphohistone H3), neuronal differentiation (doublecortin), and apoptosis (caspase 3). The number of phosphohistone H3 and doublecortin-positive cells was markedly reduced in leptin-deficient mice, but not the number of apoptotic cells, indicating that adult hippocampal neurogenesis on the level of cell proliferation was affected. In addition, dendritic spine densities of pyramidal neurons in the hippocampal area CA1 were analyzed using Golgi impregnation. However, no significant change in dendritic spine densities was noted in the obese mice. Moreover, the performance of the mice was analyzed in the open field as well as in the Morris water maze. In the open field test, obese mice showed reduced locomotor activity, but in the Morris water maze they showed similar performance compared with control animals.