Plasticity Of Inhibitory Synapses Research Articles

Astrocyte control bursting mode of spiking neuron network with memristor-implemented plasticity

A mathematical model of a spiking neuron network accompanied by astrocytes is considered. The network is composed of excitatory and inhibitory neurons with synaptic connections supplied by a memristor-based model of plasticity. Another mechanism for changing the synaptic connections involves astrocytic regulations using the concept of tripartite synapses. In the absence of memristor-based plasticity, the connections between these neurons drive the network dynamics into a burst mode, as observed in many experimental neurobiological studies when investigating living networks in neuronal cultures. The memristive plasticity implementing synaptic plasticity in inhibitory synapses results in a shift in network dynamics toward an asynchronous mode. Next,it is found that accounting for astrocytic regulation in glutamatergic excitatory synapses enable the restoration of ‘normal’ burst dynamics. The conditions and parameters of such astrocytic regulation’s impact on burst dynamics established.

Study of the influence of synaptic plasticity on the formation of a feature space by a spiking neural network

The purpose of this study is to study the influence of synaptic plasticity on excitatory and inhibitory synapses on the formation of the feature space of the input image on the excitatory and inhibitory layers of neurons in a spiking neural network. Methods. To simulate the dynamics of the neuron, the computationally efficient model “Leaky integrate-and-fire” was used. The conductance-based synapse model was used as a synaptic contact model. Synaptic plasticity in excitatory and inhibitory synapses was modeled by the classical model of time dependent synaptic plasticity. A neural network composed of them generates a feature space, which is divided into classes by a machine learning algorithm. Results. A model of a spiking neural network was built with excitatory and inhibitory layers of neurons with adaptation of synaptic contacts due to synaptic plasticity. Various configurations of the model with synaptic plasticity were considered for the problem of forming the feature space of the input image on the excitatory and inhibitory layers of neurons, and their comparison was also carried out. Conclusion. It has been shown that synaptic plasticity in inhibitory synapses impairs the formation of an image feature space for a classification task. The model constraints are also obtained and the best model configuration is selected.

GABAergic synapses onto SST and PV interneurons in the CA1 hippocampal region show cell-specific and integrin-dependent plasticity

It is known that GABAergic transmission onto pyramidal neurons shows different forms of plasticity. However, GABAergic cells innervate also other inhibitory interneurons and plasticity phenomena at these projections remain largely unknown. Several mechanisms underlying plastic changes, both at inhibitory and excitatory synapses, show dependence on integrins, key proteins mediating interaction between intra- and extracellular environment. We thus used hippocampal slices to address the impact of integrins on long-term plasticity of GABAergic synapses on specific inhibitory interneurons (containing parvalbumin, PV + or somatostatin, SST +) known to innervate distinct parts of principal cells. Administration of RGD sequence-containing peptide induced inhibitory long-term potentiation (iLTP) at fast-spiking (FS) PV + as well as on SST + interneurons. Interestingly, treatment with a more specific peptide GA(C)RRETAWA(C)GA (RRETAWA), affecting α5β1 integrins, resulted in iLTP in SST + and iLTD in FS PV + interneurons. Brief exposure to NMDA is known to induce iLTP at GABAergic synapses on pyramidal cells. Intriguingly, application of this protocol for considered interneurons evoked iLTP in SST + and iLTD in PV + interneurons. Moreover, we showed that in SST + cells, NMDA-evoked iLTP depends on the incorporation of GABAA receptors containing α5 subunit to the synapses, and this iLTP is occluded by RRETAWA peptide, indicating a key role of α5β1 integrins. Altogether, our results revealed that plasticity of inhibitory synapses at GABAergic cells shows interneuron-specificity and show differences in the underlying integrin-dependent mechanisms. This is the first evidence that neuronal disinhibition may be a highly plastic process depending on interneuron type and integrins’ activity.

Impaired formation of high-order gephyrin oligomers underlies gephyrin dysfunction-associated pathologies

SummaryGephyrin is critical for the structure, function, and plasticity of inhibitory synapses. Gephyrin mutations have been linked to various neurological disorders; however, systematic analyses of the functional consequences of these mutations are lacking. Here, we performed molecular dynamics simulations of gephyrin to predict how six reported point mutations might change the structural stability and/or function of gephyrin. Additional in silico analyses revealed that the A91T and G375D mutations reduce the binding free energy of gephyrin oligomer formation. Gephyrin A91T and G375D displayed altered clustering patterns in COS-7 cells and nullified the inhibitory synapse-promoting effect of gephyrin in cultured neurons. However, only the G375D mutation reduced gephyrin interaction with GABAA receptors and neuroligin-2 in mouse brain; it also failed to normalize deficits in GABAergic synapse maintenance and neuronal hyperactivity observed in hippocampal dentate gyrus-specific gephyrin-deficient mice. Our results provide insights into biochemical, cell-biological, and network-activity effects of the pathogenic G375D mutation.

Modulation of Coordinated Activity across Cortical Layers by Plasticity of Inhibitory Synapses

SummaryIn the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer (L) 2/3 pyramidal neurons (PNs) elicits strong feedforward inhibition (FFI) onto L5 PNs. We find that FFI involving parvalbumin (PV)-expressing cells is strongly potentiated by postsynaptic PN burst firing. FFI plasticity modifies the PN excitation-to-inhibition (E/I) ratio, strongly modulates PN gain, and alters information transfer across cortical layers. Moreover, our LTPi-inducing protocol modifies firing of L5 PNs and alters the temporal association of PN spikes to γ-oscillations both in vitro and in vivo. All of these effects are captured by unbalancing the E/I ratio in a feedforward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognition-relevant network activity.

Dynamic Regulation of GABAA Receptor Biosynthesis and Transport

γ-Aminobutyric acid (GABA) receptors are the main receptors supporting inhibition in the central nervous system. These receptors are divided into the ionotropic (GABAA, ion channels) and metabotropic (GABAB, coupled with G proteins) types. Activation of GABAA receptors is the main source of rapid inhibition in the central nervous system. This review addresses dynamic regulation of the delivery of GABAA receptors on formation of inhibitory synapses. The plasticity of inhibitory synapses in regulating the attachment of receptors within them is not discussed. Impairments to the regulation of GABAA receptors has been described in diseases such as epilepsy, anxiety disorders, schizophrenia, and alcoholism. Thus, studies of the biogenesis of GABAA receptors, their dynamic regulation, and their role in the etiology of various diseases are important prerequisites for the development of novel therapeutic strategies.

Nanoscale Molecular Reorganization of the Inhibitory Postsynaptic Density Is a Determinant of GABAergic Synaptic Potentiation.

Gephyrin is a key scaffold protein mediating the anchoring of GABAA receptors at inhibitory synapses. Here, we exploited superresolution techniques combined with proximity-based clustering analysis and model simulations to investigate the single-molecule gephyrin reorganization during plasticity of inhibitory synapses in mouse hippocampal cultured neurons. This approach revealed that, during the expression of inhibitory LTP, the increase of gephyrin density at postsynaptic sites is associated with the promoted formation of gephyrin nanodomains. We demonstrate that the gephyrin rearrangement in nanodomains stabilizes the amplitude of postsynaptic currents, indicating that, in addition to the number of synaptic GABAA receptors, the nanoscale distribution of GABAA receptors in the postsynaptic area is a crucial determinant for the expression of inhibitory synaptic plasticity. In addition, the methodology implemented here clears the way to the application of the graph-based theory to single-molecule data for the description and quantification of the spatial organization of the synapse at the single-molecule level.SIGNIFICANCE STATEMENT The mechanisms of inhibitory synaptic plasticity are poorly understood, mainly because the size of the synapse is below the diffraction limit, thus reducing the effectiveness of conventional optical and imaging techniques. Here, we exploited superresolution approaches combined with clustering analysis to study at unprecedented resolution the distribution of the inhibitory scaffold protein gephyrin in response to protocols inducing LTP of inhibitory synaptic responses (iLTP). We found that, during the expression of iLTP, the increase of synaptic gephyrin is associated with the fragmentation of gephyrin in subsynaptic nanodomains. We demonstrate that such synaptic gephyrin nanodomains stabilize the amplitude of inhibitory postsynaptic responses, thus identifying the nanoscale gephyrin rearrangement as a key determinant for inhibitory synaptic plasticity.

The Impact of Structural Heterogeneity on Excitation-Inhibition Balance in Cortical Networks

SummaryModels of cortical dynamics often assume a homogeneous connectivity structure. However, we show that heterogeneous input connectivity can prevent the dynamic balance between excitation and inhibition, a hallmark of cortical dynamics, and yield unrealistically sparse and temporally regular firing. Anatomically based estimates of the connectivity of layer 4 (L4) rat barrel cortex and numerical simulations of this circuit indicate that the local network possesses substantial heterogeneity in input connectivity, sufficient to disrupt excitation-inhibition balance. We show that homeostatic plasticity in inhibitory synapses can align the functional connectivity to compensate for structural heterogeneity. Alternatively, spike-frequency adaptation can give rise to a novel state in which local firing rates adjust dynamically so that adaptation currents and synaptic inputs are balanced. This theory is supported by simulations of L4 barrel cortex during spontaneous and stimulus-evoked conditions. Our study shows how synaptic and cellular mechanisms yield fluctuation-driven dynamics despite structural heterogeneity in cortical circuits.

The plasticity of inhibitory synapses as a factor of long-term modifications

We review the current data on the functions of GABAergic inhibition in the mechanisms of long-term plasticity that underlie learning and memory. We present the main principles of the organization of the inhibitory inputs and molecular composition of synapses. So-called “ionic plasticity” is a specific feature of the inhibitory synapses. The range of ionic plasticity that is associated with the depolarizing effect of GABA is of particular interest. In adult animals, this effect is observed after high-frequency stimulation of synaptic inputs. The main attention was focused on the reaction of disinhibition in the hippocampus that is induced by high-frequency stimulation of the afferent inputs that are used for LTP induction. We argue that the disinhibition effect is crucially important for more effective consolidation of long-term modifications, including structural plasticity.

Functional Role of ATP Binding to Synapsin I In Synaptic Vesicle Trafficking and Release Dynamics

Synapsins (Syns) are synaptic vesicle (SV)-associated proteins involved in the regulation of synaptic transmission and plasticity, which display a highly conserved ATP binding site in the central C-domain, whose functional role is unknown. Using molecular dynamics simulations, we demonstrated that ATP binding to SynI is mediated by a conformational transition of a flexible loop that opens to make the binding site accessible; such transition, prevented in the K269Q mutant, is not significantly affected in the absence of Ca(2+) or by the E373K mutation that abolishes Ca(2+)-binding. Indeed, the ATP binding to SynI also occurred under Ca(2+)-free conditions and increased its association with purified rat SVs regardless of the presence of Ca(2+) and promoted SynI oligomerization. However, although under Ca(2+)-free conditions, SynI dimerization and SV clustering were enhanced, Ca(2+) favored the formation of tetramers at the expense of dimers and did not affect SV clustering, indicating a role of Ca(2+)-dependent dimer/tetramer transitions in the regulation of ATP-dependent SV clustering. To elucidate the role of ATP/SynI binding in synaptic physiology, mouse SynI knock-out hippocampal neurons were transduced with either wild-type or K269Q mutant SynI and inhibitory transmission was studied by patch-clamp and electron microscopy. K269Q-SynI expressing inhibitory synapses showed increased synaptic strength due to an increase in the release probability, an increased vulnerability to synaptic depression and a dysregulation of SV trafficking, when compared with wild-type SynI-expressing terminals. The results suggest that the ATP-SynI binding plays predocking and postdocking roles in the modulation of SV clustering and plasticity of inhibitory synapses.

Rebound potentiation of inhibition in juvenile visual cortex requires vision-induced BDNF expression.

The developmental increase in the strength of inhibitory synaptic circuits defines the time window of the critical period for plasticity in sensory cortices. Conceptually, plasticity of inhibitory synapses is an attractive mechanism to allow for homeostatic adaptation to the sensory environment. However, a brief duration of visual deprivation that causes maximal change in excitatory synapses produces minimal change in inhibitory synaptic transmission. Here we examined developmental and experience-dependent changes in inhibition by measuring miniature IPSCs (mIPSCs) in layer 2/3 pyramidal neurons of mouse visual cortex. During development from postnatal day 21 (P21) to P35, GABAA receptor function changed from fewer higher-conductance channels to more numerous lower-conductance channels without altering the average mIPSC amplitude. Although a week of visual deprivation did not alter the average mIPSC amplitude, a subsequent 2 h exposure to light produced a rapid rebound potentiation. This form of plasticity is restricted to a critical period before the developmental change in GABAergic synaptic properties is completed, and hence is absent by P35. Visual experience-dependent rebound potentiation of mIPSCs is accompanied by an increase in the open channel number and requires activity-dependent transcription of brain-derived neurotrophic factor (BDNF). Mice lacking BDNF transcription through promoter IV did not show developmental changes in inhibition and lacked rebound potentiation. Our results suggest that sensory experience may have distinct functional consequences in normal versus deprived sensory cortices, and that experience-dependent BDNF expression controls the plasticity of inhibitory synaptic transmission particularly when recovering vision during the critical period.

Activity-dependent adaptations in inhibitory axons

Synaptic connections in our brains change continuously and throughout our lifetime. Despite ongoing synaptic changes, a healthy balance between excitation and inhibition is maintained by various forms of homeostatic and activity-dependent adaptations, ensuring stable functioning of neuronal networks. In this review we summarize experimental evidence for activity-dependent changes occurring in inhibitory axons, in cultures as well as in vivo. Axons form many presynaptic terminals, which are dynamic structures sharing presynaptic material along the axonal shaft. We discuss how internal (e.g., vesicle sharing) and external factors (e.g., binding of cell adhesion molecules or secreted factors) may affect the formation and plasticity of inhibitory synapses.

Sensible Balance

The activities of cortical neurons are controlled through the plasticity of inhibitory synapses.

Activity-dependent coordinated mobility of hippocampal inhibitory synapses visualized with presynaptic and postsynaptic tagged-molecular markers

Axonal varicosities and dendritic spines at excitatory synapses are dynamic structures essential for synaptic plasticity, whereas the behavior of inhibitory synapses during development and plasticity remains largely unknown. To investigate the morphology and dynamics of inhibitory synapses, we used two distinct pre- and postsynaptic fluorescent probes: one is a yellow fluorescent protein, Venus, incorporated into vesicular GABA transporter (VGAT) gene as a specific marker of presynaptic inhibitory neurons and the other red fluorescent protein (mCherry)-tagged gephyrin, a postsynaptic scaffolding protein, as a postsynaptic marker. Using primary culture of mouse hippocampal neurons and confocal laser-scanning microscopy, we established a system by which close contacts of Venus-positive axonal varicosities with mCherry-labeled gephyrin clusters in the dendritic shafts of dissociated hippocampal pyramidal neurons could be clearly visualized. Time-lapse imaging revealed that: (1) the presynaptic varicosities actively moved with marked changes in their shapes, and the postsynaptic scaffolding protein gephyrin clusters underwent coordinated movements in a tight association with the presynaptic varicosities, (2) the extents of morphological changes and movements depended on the developmental stages, reaching a stable level as the inhibitory synaptic connections matured, and (3) the motility indexes of the varicosity and its counterpart gephyrin cluster were well correlated. Furthermore, action potential blockade with tetrodotoxin treatment reduced the varicosity size, gephyrin cluster mobility as well as the amplitude of GABAergic synaptic currents in pyramidal neurons. Such a neural activity-dependent dynamic change in GABAergic synaptic morphology is likely to play a critical role in the regulatory mechanism underlying the formation and plasticity of inhibitory synapses.

Inhibitory plasticity underlies visual deprivation-induced loss of receptive field refinement in the adult superior colliculus

Increasing evidence shows that sensory experience is not necessary for initial patterning of neural circuitry but is essential for maintenance and plasticity. We have investigated the role of visual experience in development and plasticity of inhibitory synapses in the retinocollicular pathway of an altricial rodent, the Syrian hamster. We reported previously that visual receptive field (RF) refinement in superior colliculus (SC) occurs with the same time course in long-term dark-reared (LTDR) as in normally-reared hamsters, but RFs in LTDR animals become unrefined in adulthood. Here we provide support for the hypothesis that this failure to maintain refined RFs into adulthood results from inhibitory plasticity at both pre- and postsynaptic levels. Iontophoretic application of gabazine, a GABA(A) receptor antagonist, or muscimol, a GABA(A) receptor agonist, had less of an effect on RF size and excitability of adult LTDR animals than in short-term DR animals or normal animals. Consistent with these physiological observations, the percentage of GABA-immunoreactive neurons was significantly decreased in the SC of LTDR animals compared to normal animals and to animals exposed to a normal light cycle early in development, before LTDR. Thus GABAergic inhibition in the SC of LTDR animals is reduced, weakening the inhibitory surround and contributing significantly to the visual deprivation-induced enlargement of RFs seen. Our results argue that early visually-driven activity is necessary to maintain the inhibitory circuitry intrinsic to the adult SC and to protect against the consequences of visual deprivation.

Visual perception of ambiguous figures: synchronization based neural models

We develop and study two neural network models of perceptual alternations. Both models have a star-like architecture of connections with a central element connected to a set of peripheral elements. A particular perception is simulated in terms of partial synchronization between the central element and some sub-group of peripheral elements. The first model is constructed from phase oscillators and the mechanism of perceptual alternations is based on chaotic intermittency under fixed parameter values. Similar to experimental evidence, the distribution of times between perceptual alternations is represented by the gamma distribution. The second model is built of spiking neurons of the Hodgkin-Huxley type. The mechanism of perceptual alternations is based on plasticity of inhibitory synapses which increases the inhibition from the central unit to the neural assembly representing the current percept. As a result another perception is formed. Simulations show that the second model is in good agreement with behavioural data on switching times between percepts of ambiguous figures and with experimental results on binocular rivalry of two and four percepts.

A neural circuit model forming semantic network with exception using spike-timing-dependent plasticity of inhibitory synapses

We propose a neural circuit model forming a semantic network with exceptions using the spike-timing-dependent plasticity (STDP) of inhibitory synapses. To evaluate the proposed model, we conducted nine types of computer simulation by combining the three STDP rules for inhibitory synapses and the three spike pairing rules. The simulation results obtained with the STDP rule for inhibitory synapses by Haas et al. [Haas, J.S., Nowotny, T., Abarbanel, H.D.I., 2006, Spike-timing-dependent plasticity of inhibitory synapses in the entorhinal cortex. J. Neurophysiol. 96, 3305–3313] are successful, whereas, the other results are unsuccessful. The results and examinations suggested that the inhibitory connection from the concept linked with an exceptional feature to the general feature is necessary for forming a semantic network with an exception.

Spike-Timing-Dependent Plasticity of Inhibitory Synapses in the Entorhinal Cortex

Actions of inhibitory interneurons organize and modulate many neuronal processes, yet the mechanisms and consequences of plasticity of inhibitory synapses remain poorly understood. We report on spike-timing-dependent plasticity of inhibitory synapses in the entorhinal cortex. After pairing presynaptic stimulations at time t(pre) with evoked postsynaptic spikes at time t(post) under pharmacological blockade of excitation we found, via whole cell recordings, an asymmetrical timing rule for plasticity of the remaining inhibitory responses. Strength of response varied as a function of the time interval Deltat = t(post) - t(pre): for Deltat > 0 inhibitory responses potentiated, peaking at a delay of 10 ms. For Deltat < 0, the synaptic coupling depressed, again with a maximal effect near 10 ms of delay. We also show that changes in synaptic strength depend on changes in intracellular calcium concentrations and demonstrate that the calcium enters the postsynaptic cell through voltage-gated channels. Using network models, we demonstrate how this novel form of plasticity can sculpt network behavior efficiently and with remarkable flexibility.

Effects of extracellular concentration of calcium and intensity of stimulation on short-term plasticity in single inhibitory synapses between cultured hippocampal neurons

We studied the characteristics of short-term plasticity in inhibitory synapses of cultured neurons of the rat hippocampus. In our experiments, we used techniques of voltage clamp in the whole-cell configuration and of local electrical stimulation (pairs of stimuli were applied to a single synaptic terminal of the GABA-ergic neuron under conditions of the blockade of spreading excitation). We demonstrated that an increase or a decrease in the extracellular concentration of calcium ions ([Ca2+]o) results in modifications of the pattern of this plasticity. Depression of the second postsynaptic response under conditions of normal [Ca2+]o was characterized by a paired-pulse ratio (PPR) equal, on average, to 0.78 ± 0.04 (n = 5). With a decrease in the [Ca2+]o to 0.5 mM, depression was changed to facilitation (PPR = 1.17 ± 0.08, n = 5), while with a rise in the [Ca2+]o to 5.0 mM, depression became more clearly pronounced (PPR = 0.48 ± 0.03, n = 5). Alterations of responses, which were determined by a decrease or an increase in the [Ca2+]o, differed significantly from those related to a decrease or an increase in the amplitude of presynaptic stimulation. Analysis of the parameters of the pairs of evoked inhibitory postsynaptic currents under conditions of various [Ca2+]o and different intensities of stimulation of the presynaptic terminal allows us to conclude that in these terminals calcium-dependent (and, probably, also voltage-dependent) mechanisms underlying control of short-term synaptic plasticity are present.

Differential induction of long term synaptic plasticity in inhibitory synapses of the hippocampus

Long term synaptic plasticity has been more extensively studied in excitatory synapses, but it is also a property of inhibitory synapses. Many inhibitory synapses target hippocampal pyramidal neurons of the CA1 region. They originate from several interneuron classes that subdivide the surface area that they target on the pyramidal cell. Thus, many interneurons preferentially innervate the perisomatic area and axon hillock of the pyramidal cells while others preferentially target dendritic branches and spines. Methods to preferentially activate dendritic or somatic inhibitory synapses onto pyramidal neurons have been devised. By using these methods, the present work demonstrates that a stimulation pattern that induces long term potentiation (LTP) in excitatory synapses of the Schaffer collaterals is also capable of inducing distinct types of long term plastic changes in different classes of inhibitory synapses: Induction of long term depression (LTD) was seen in dendritic inhibitory synapses whereas LTP was observed in somatic inhibitory synapses. These findings suggest that inhibitory synapses arising from different interneuron classes may respond to the same stimulus according to their specific plastic potential enabling a spatial combinatorial pattern of inhibitory effects onto the pyramidal cell.