scholarly journals Computational models reveal how chloride dynamics determine the optimal distribution of inhibitory synapses to minimise dendritic excitability

2021 ◽  
Author(s):  
Christopher Brian Currin ◽  
Joseph Valentino Raimondo
Keyword(s):  
Computational Models ◽  
Reversal Potential ◽  
Chloride Ion ◽  
Excitatory Input ◽  
Inhibitory Synapses ◽  
Inhibitory Influence ◽  
Synaptic Inhibition ◽  
Dendritic Excitability ◽  
Gabaergic Synapses ◽  
Targeted Inhibition

AbstractMany neurons in the mammalian central nervous system have complex dendritic arborisations and active dendritic conductances that enable these cells to perform sophisticated computations. How dendritically targeted inhibition affects local dendritic excitability is not fully understood. Here we use computational models of branched dendrites to investigate where GABAergic synapses should be placed to minimise dendritic excitability over time. To do so, we formulate a metric we term the “Inhibitory Level” (IL), which quantifies the effectiveness of synaptic inhibition for reducing the depolarising effect of nearby excitatory input. GABAergic synaptic inhibition is dependent on the reversal potential for GABAA receptors (EGABA), which is primarily set by the transmembrane chloride ion (Cl-) concentration gradient. We, therefore, investigated how variable EGABA and dynamic chloride affects dendritic inhibition. We found that the inhibitory effectiveness of dendritic GABAergic synapses accumulates at an encircled branch junction. The extent of inhibitory accumulation is dependent on the number of branches and location of synapses but is independent of EGABA. This accumulation occurs even for very distally placed inhibitory synapses when they are hyperpolarising – but not when they are shunting. When accounting for Cl- fluxes and dynamics in Cl- concentration, we observed that Cl- loading is detrimental to inhibitory effectiveness. This enabled us to determine the most inhibitory distribution of GABAergic synapses which is close to – but not at – a shared branch junction. This distribution balances a trade-off between a stronger combined inhibitory influence when synapses closely encircle a branch junction with the deleterious effects of increased Cl- loading that occurs when inhibitory synapses are co-located.

scholarly journals Chloride dynamics alter the input-output properties of neurons

2019 ◽  
Author(s):  
Christopher B. Currin ◽  
Andrew J. Trevelyan ◽  
Colin J. Akerman ◽  
Joseph V. Raimondo
Keyword(s):  
Chloride Concentration ◽  
Reversal Potential ◽  
Chloride Ions ◽  
Inhibitory Synapses ◽  
Synaptic Inhibition ◽  
Output Function ◽  
Input Output ◽  
Subcellular Targeting ◽  
The Brain ◽  
Neuronal Output

AbstractFast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were entirely mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.Author SummaryThe fundamental unit of computation in the brain is the neuron, whose output reflects information within the brain. A determining factor in the transfer and processing of information in the brain is the modulation of activity by inhibitory synaptic inputs. Fast synaptic inhibition is mediated by the neurotransmitter GABA binding to GABAA receptors, which are permeable to chloride ions. How changes in chloride ion concentration affect neuronal output is an important consideration for information flow in the brain that is currently not being thoroughly investigated. In this research, we used multi-compartmental models of neurons to link the deleterious effects that accumulation of chloride ions can have on inhibitory signalling with changes in neuronal ouput. Together, our results highlight the importance of accounting for changes in chloride concentration in theoretical and computer-based models that seek to explore the computational properties of inhibition.

GABA responses in rat dentate granule neurons are mediated by chloride

1988 ◽  
Vol 66 (5) ◽  
pp. 637-642 ◽  
Author(s):  
Timothy J. Blaxter ◽  
Peter L. Carlen
Keyword(s):  
Granule Cells ◽  
Hippocampal Slices ◽  
Reversal Potential ◽  
Chloride Ion ◽  
Chloride Ions ◽  
Ion Concentration ◽  
Aminobutyric Acid ◽  
Granule Neurons ◽  
Nernst Equation ◽  
Central Neurons

The dendrites of granule cells in hippocampal slices responded to γ-aminobutyric acid (GABA) with a depolarization. The response was blocked by picrotoxin in a noncompetitive manner. Reductions in the extracellular chloride ion concentration changed the reversal potential of the response by an amount predicted from the Nernst equation for chloride ion. Chloride-dependent hyperpolarizing responses were sometimes also found in the cell body of the granule cells. Since the reversal potential followed that predicted from the Nernst equation for chloride, we conclude that the response was mediated by chloride ions alone with no contribution from other ions. This has not previously been shown for the depolarizing response to GABA in central neurons.

Mechanisms of neocortical epileptogenesis in vitro

1982 ◽  
Vol 48 (6) ◽  
pp. 1321-1335 ◽  
Author(s):  
M. J. Gutnick ◽  
B. W. Connors ◽  
D. A. Prince
Keyword(s):  
Reversal Potential ◽  
Excitatory Input ◽  
Short Latency ◽  
Resting Potential ◽  
Excitatory Postsynaptic Potential ◽  
Cellular Mechanisms ◽  
Voltage Dependent ◽  
Intact Cortex

1. The cellular mechanisms underlying interictal epileptogenesis have been examined in an in vitro slice preparation of guinea pig neocortex. Penicillin or bicuculline was applied to the tissue, and intracellular recordings were obtained from neurons and glia. 2. Following convulsant application, stimulation could elicit a short-latency excitatory postsynaptic potential (EPSP) and a large, longer latency depolarization shift (DS) in single neurons. DSs in neurons of the slice were very similar to those evoked in neurons of neocortex in vivo in that they displayed an all-or-none character, large shifts in latency during repetitive stimuli, long afterpotentials, and a prolonged refractory period. In contrast to epileptogenesis produced by penicillin in intact cortex, neither spontaneous DSs nor ictal episodes were observed in neocortical slices. 3. In simultaneous recordings from pairs of neurons within the same cortical column, DS generation and latency shifts were invariably synchronous. DS generation in neurons was also coincident with large, paroxysmal increases of extracellular [K+], as indicated by simultaneous recordings from glia. 4. When polarizing currents were applied to neurons injected with the local anesthetic QX-314, the DS amplitude varied monotonically and had an extrapolated reversal potential near 0 mV. In neurons injected with the K+-current blocker Cs+, large displacements of membrane potential were possible, and both the short-latency EPSP and the peak of the DS diminished completely at about 0 mV. At potentials positive to this, the short-latency EPSP was reversed, and the DS was replaced by a paroxysmal hyperpolarization whose rise time and peak latency were prolonged compared to the DS evoked at resting potential. The paroxysmal hyperpolarization probably represents the prolonged activation of the impaled neuron by EPSPs. 5. Voltage-dependent components, including slow spikes, appeared to contribute to generation of the DS at resting potential in Cs+-filled cells, and these components were blocked during large depolarizations. 6. The results suggest that DS generation in single neocortical neurons occurs during synchronous synaptic activation of a large group of cells. DS onset in a given neuron is determined by the timing of a variable-latency excitatory input that differs from the short-latency EPSP. The DS slow envelope appears to be generated by long-duration excitatory synaptic currents and may be modulated by intrinsic voltage-dependent membrane conductances. 7. We present a hypothesis for the initiation of the DS, based on the anatomical and physiological organization of the intrinsic neocortical circuits.

scholarly journals Reversing GABA polarity corrects synaptic physiology and behavioural deficits in young adolescent Syngap1+/- mice

2021 ◽  
Author(s):  
Vijaya Verma ◽  
MJ Vijay Kumar ◽  
Kavita Sharma ◽  
Sridhar Rajaram ◽  
Ravi Muddashetty ◽  
...  
Keyword(s):  
Small Molecule ◽  
Intraperitoneal Administration ◽  
Chloride Concentration ◽  
Reversal Potential ◽  
Autism Spectrum ◽  
Ion Concentration ◽  
Pharmacological Intervention ◽  
Subsequent Increase ◽  
Intracellular Chloride ◽  
Gabaergic Synapses

Abstract Haploinsufficiency in SYNGAP1 is implicated in Intellectual Disability (ID) and Autism Spectrum disorder (ASD) and affects the maturation of dendritic spines. The abnormal spine development has been suggested to cause disbalance of excitatory and inhibitory (E/I) neurotransmission at distinct developmental periods. In addition, E/I imbalances in Syngap1+/- mice might be due to abnormalities in K+-Cl- co-transporter function (NKCC1, KCC2), in a similar manner as in the murine models of Fragile-X and Rett syndromes. To study whether an altered intracellular chloride ion concentration represents an underlying mechanism of altered function of GABAergic synapses in Dentate Gyrus Granule Cells of Syngap1+/- recordings were performed at different developmental stages of the mice. We observed that neurons at P14-15 of Syngap1+/- mice had depolarised membrane potential and a decreased Cl- reversal potential. The KCC2 expression was decreased compared to Wild-type (WT) mice at P14-15. Furtherly, the small molecule GSK-3β inhibitor, 6-bromoindirubin-3`-oxime (6BIO), was tested in an attempt to restore the function of GABAergic synapses. We discovered that intraperitoneal administration of 6BIO during the critical period or young adolescents normalized an altered E/I balance, the deficits of synaptic transmission, and behavioral performance like social novelty, anxiety, and memory of the Syngap1+/- mice. In summary, altered functionality of GABAergic synapses in Syngap1+/- mice is based on a reduced KCC2 expression and a subsequent increase in the intracellular chloride concentration that can be counteracted by the small molecule 6BIO. The 6BIO sufficiently restored cognitive, emotional, and social symptoms by pharmacological intervention, particularly, in adulthood.

scholarly journals Nitric Oxide Transiently Converts Synaptic Inhibition to Excitation in Retinal Amacrine Cells

2006 ◽  
Vol 95 (5) ◽  
pp. 2866-2877 ◽  
Author(s):  
Brian Hoffpauir ◽  
Emily McMains ◽  
Evanna Gleason
Keyword(s):  
Nitric Oxide ◽  
Hippocampal Neurons ◽  
Reversal Potential ◽  
Amacrine Cells ◽  
Cell Types ◽  
Synaptic Function ◽  
Positive Shift ◽  
Gabaergic Synapses ◽  
Multiple Cell

Nitric oxide (NO) is generated by multiple cell types in the vertebrate retina, including amacrine cells. We investigate the role of NO in the modulation of synaptic function using a culture system containing identified retinal amacrine cells. We find that moderate concentrations of NO alter GABAA receptor function to produce an enhancement of the GABA-gated current. Higher concentrations of NO also enhance GABA-gated currents, but this enhancement is primarily due to a substantial positive shift in the reversal potential of the current. Several pieces of evidence, including a similar effect on glycine-gated currents, indicate that the positive shift is due to an increase in cytosolic Cl−. This change in the chloride distribution is especially significant because it can invert the sign of GABA- and glycine-gated voltage responses. Furthermore, current- and voltage-clamp recordings from synaptic pairs of GABAergic amacrine cells demonstrate that NO transiently converts signaling at GABAergic synapses from inhibition to excitation. Persistence of the NO-induced shift in ECl− in the absence of extracellular Cl− indicates that the increase in cytosolic Cl− is due to release of Cl− from an internal store. An NO-dependent release of Cl− from an internal store is also demonstrated for rat hippocampal neurons indicating that this mechanism is not restricted to the avian retina. Thus signaling in the CNS can be fundamentally altered by an NO-dependent mobilization of an internal Cl− store.

scholarly journals A model of order-selectivity based on dynamic changes in the balance of excitation and inhibition produced by short-term synaptic plasticity

2015 ◽  
Vol 113 (2) ◽  
pp. 509-523 ◽  
Author(s):  
Vishwa Goudar ◽  
Dean V. Buonomano
Keyword(s):  
Synaptic Plasticity ◽  
Computational Models ◽  
Experimental Studies ◽  
Inhibitory Synapses ◽  
Speech Discrimination ◽  
Short Term ◽  
Dynamic Changes ◽  
Short Term Plasticity ◽  
Underlying Mechanisms ◽  
Parametric Analyses

Determining the order of sensory events separated by a few hundred milliseconds is critical to many forms of sensory processing, including vocalization and speech discrimination. Although many experimental studies have recorded from auditory order-sensitive and order-selective neurons, the underlying mechanisms are poorly understood. Here we demonstrate that universal properties of cortical synapses—short-term synaptic plasticity of excitatory and inhibitory synapses—are well suited for the generation of order-selective neural responses. Using computational models of canonical disynaptic circuits, we show that the dynamic changes in the balance of excitation and inhibition imposed by short-term plasticity lead to the generation of order-selective responses. Parametric analyses predict that among the forms of short-term plasticity expressed at excitatory-to-excitatory, excitatory-to-inhibitory, and inhibitory-to-excitatory synapses, the single most important contributor to order-selectivity is the paired-pulse depression of inhibitory postsynaptic potentials (IPSPs). A topographic model of the auditory cortex that incorporates short-term plasticity accounts for both context-dependent suppression and enhancement in response to paired tones. Together these results provide a framework to account for an important computational problem based on ubiquitous synaptic properties that did not yet have a clearly established computational function. Additionally, these studies suggest that disynaptic circuits represent a fundamental computational unit that is capable of processing both spatial and temporal information.

Synaptically Released GABA Activates Both Pre- and Postsynaptic GABAB Receptors in the Rat Globus Pallidus

2005 ◽  
Vol 94 (2) ◽  
pp. 1104-1114 ◽  
Author(s):  
Katsuyuki Kaneda ◽  
Hitoshi Kita
Keyword(s):  
Globus Pallidus ◽  
Reversal Potential ◽  
Gaba Release ◽  
Gabab Receptors ◽  
Equilibrium Potential ◽  
Postsynaptic Currents ◽  
Gabaergic Synapses ◽  
Rat Brain Slice ◽  
Whole Cell Recordings ◽  
Local Stimulation

The globus pallidus (GP) contains abundant GABAergic synapses and GABAB receptors. To investigate whether synaptically released GABA can activate pre- and postsynaptic GABAB receptors in the GP, physiological recordings were performed using rat brain slice preparations. Cell-attached recordings from GABAA antagonist-treated preparations revealed that repetitive local stimulation induced a GABAB antagonist-sensitive pause in spontaneous firings of GP neurons. Whole cell recordings revealed that the repetitive stimulation evoked fast excitatory postsynaptic potentials followed by a slow inhibitory postsynaptic potential (IPSP) in GP neurons. The slow IPSP was insensitive to a GABAA receptor antagonist, increased in amplitude with the application of ionotropic glutamate receptor antagonists, and was suppressed by the GABAB antagonist CGP55845 . The reversal potential of the slow IPSP was close to the potassium equilibrium potential. These results suggest that synaptically released GABA activated postsynaptic GABAB receptors and induced the pause and the slow IPSP. On the other hand, in the neurons that were treated to block postsynaptic GABAB responses, CGP55845 increased the amplitudes of repetitive local stimulation-induced GABAA-mediated inhibitory postsynaptic currents (IPSCs) but not the ionotropic glutamate-mediated excitatory postsynaptic currents. Moreover, the GABAB receptor specific agonist baclofen reduced the frequency of miniature IPSCs without altering their amplitude distributions. These results suggest that synaptically released GABA also activated presynaptic GABAB autoreceptors, resulting in decreased GABA release in the GP. Together, we infer that both pre- and postsynaptic GABAB receptors may play crucial roles in the control of GP neuronal activity.

Modulatory Effects of Serotonin on GABAergic Synaptic Transmission and Membrane Properties in the Deep Cerebellar Nuclei

2009 ◽  
Vol 101 (3) ◽  
pp. 1361-1374 ◽  
Author(s):  
Fumihito Saitow ◽  
Mitsumasa Murano ◽  
Hidenori Suzuki
Keyword(s):  
Conditioning Stimulus ◽  
Cerebellar Nuclei ◽  
Membrane Properties ◽  
Inhibitory Synapses ◽  
Slow Inward Current ◽  
Deep Cerebellar Nuclei ◽  
Spike Generation ◽  
Inhibitory Transmission ◽  
Inward Current ◽  
Gabaergic Synapses

Cerebellar outputs from the deep cerebellar nuclei (DCN) are critical for generating and controlling movement. DCN neuronal activity is primarily controlled by GABAergic inhibitory transmission by Purkinje cells in the cerebellar cortex and is also modulated by nerve inputs originating from other brain regions within and outside the cerebellum. In this study, we examined the modulatory effects of 5-HT on GABAergic synapses in the DCN. 5-HT decreased the amplitude of stimulation-evoked inhibitory postsynaptic currents (eIPSCs) in DCN neurons, and this effect was abolished by a 5-HT1B antagonist, SB 224289. The decrease in IPSC amplitude was associated with an increased paired-pulse ratio of the IPSC. 5-HT also decreased the frequency of miniature IPSCs without altering the amplitude. These data suggest that 5-HT presynaptically inhibited GABA release. Furthermore, 5-HT elicited a slow inward current in DCN neurons. Pharmacological studies showed that 5-HT activated the 5-HT5 receptor, which is positively coupled to G protein and elicited the slow inward current through enhancement of hyperpolarization-activated cation channel activation. Finally, we examined the effects of 5-HT on the spike generation that accompanies repetitive stimulation of inhibitory synapses. 5-HT increased the spontaneous firing rate in DCN neurons caused by depolarization. Increase in the 5-HT–induced tonic firing relatively decreased the contrast difference from the rebound depolarization-induced firing. However, the inhibitory transmission-induced silencing of DCN firing remained during the conditioning stimulus. These results suggest that 5-HT plays a regulatory role in spike generation and contributes to the gain control of inhibitory GABAergic synapses in DCN neurons.

scholarly journals Deletion of PLCγ1 in GABAergic neurons increases seizure susceptibility in aged mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hye Yun Kim ◽  
Yong Ryoul Yang ◽  
Hongik Hwang ◽  
Ha-Eun Lee ◽  
Hyun-Jun Jang ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Molecular Mechanisms ◽  
Gabaergic Neurons ◽  
Inhibitory Synapses ◽  
Synaptic Inhibition ◽  
Behavioral Alterations ◽  
Inhibitory Synaptic Transmission ◽  
Aged Mice ◽  
Phospholipase Cγ1 ◽  
Genetic Deletion

AbstractSynaptic inhibition plays a fundamental role in the information processing of neural circuits. It sculpts excitatory signals and prevents hyperexcitability of neurons. Owing to these essential functions, dysregulated synaptic inhibition causes a plethora of neurological disorders, including epilepsy, autism, and schizophrenia. Among these disorders, epilepsy is associated with abnormal hyperexcitability of neurons caused by the deficits of GABAergic neuron or decreased GABAergic inhibition at synapses. Although many antiepileptic drugs are intended to improve GABA-mediated inhibition, the molecular mechanisms of synaptic inhibition regulated by GABAergic neurons are not fully understood. Increasing evidence indicates that phospholipase Cγ1 (PLCγ1) is involved in the generation of seizure, while the causal relationship between PLCγ1 and seizure has not been firmly established yet. Here, we show that genetic deletion of PLCγ1 in GABAergic neurons leads to handling-induced seizure in aged mice. In addition, aged Plcg1F/F; Dlx5/6-Cre mice exhibit other behavioral alterations, including hypoactivity, reduced anxiety, and fear memory deficit. Notably, inhibitory synaptic transmission as well as the number of inhibitory synapses are decreased in the subregions of hippocampus. These findings suggest that PLCγ1 may be a key determinant of maintaining both inhibitory synapses and synaptic transmission, potentially contributing to the regulation of E/I balance in the hippocampus.

scholarly journals Estradiol modulates the efficacy of synaptic inhibition by decreasing the dwell time of GABAA receptors at inhibitory synapses

2017 ◽  
Vol 114 (44) ◽  
pp. 11763-11768 ◽  
Author(s):  
Jayanta Mukherjee ◽  
Ross A. Cardarelli ◽  
Yasmine Cantaut-Belarif ◽  
Tarek Z. Deeb ◽  
Deepak P. Srivastava ◽  
...  
Keyword(s):  
Cell Biology ◽  
Dwell Time ◽  
Critical Role ◽  
Hippocampal Slices ◽  
Dendritic Morphology ◽  
Single Particle Tracking ◽  
Adult Brain ◽  
Inhibitory Synapses ◽  
Synaptic Inhibition ◽  
Neuronal Inhibition

Estrogen plays a critical role in many physiological processes and exerts profound effects on behavior by regulating neuronal excitability. While estrogen has been established to exert effects on dendritic morphology and excitatory neurotransmission its role in regulating neuronal inhibition is poorly understood. Fast synaptic inhibition in the adult brain is mediated by specialized populations of γ-c aA receptors (GABAARs) that are selectively enriched at synapses, a process dependent upon their interaction with the inhibitory scaffold protein gephyrin. Here we have assessed the role that estradiol (E2) plays in regulating the dynamics of GABAARs and stability of inhibitory synapses. Treatment of cultured cortical neurons with E2 reduced the accumulation of GABAARs and gephyrin at inhibitory synapses. However, E2 exposure did not modify the expression of either the total or the plasma membrane GABAARs or gephyrin. Mechanistically, single-particle tracking revealed that E2 treatment selectively reduced the dwell time and thereby decreased the confinement of GABAARs at inhibitory synapses. Consistent with our cell biology measurements, we observed a significant reduction in amplitude of inhibitory synaptic currents in both cultured neurons and hippocampal slices exposed to E2, while their frequency was unaffected. Collectively, our results suggest that acute exposure of neurons to E2 leads to destabilization of GABAARs and gephyrin at inhibitory synapses, leading to reductions in the efficacy of GABAergic inhibition via a postsynaptic mechanism.

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