Chloride dynamics alter the input-output properties of neurons

Abstract

Fast 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 inputoutput 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 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.

Coincident glutamatergic depolarizations enhance GABAAreceptor-dependent Cl-influx in mature and suppress Cl-efflux in immature neurons

“…The present study demonstrates that glutamatergic co-stimulation enhances the GABAergic Cl --influx and thus enhances the activity-dependent [Cl -]i increase, as has recently been shown in-vitro [32] and insilico [33]. As a consequence, the inhibitory action of GABA may be even more impaired upon a co-activation of glutamate receptors [33]. The high basal [Cl -]i in immature neurons leads to GABAergic Cl --efflux and thus to a decrease in [Cl -]i upon GABAergic activation [18,43].…”

“…Glutamatergic co-stimulation had a direct effect on the GABAergic In this study we investigated the effect of co-activation of glutamatergic AMPA receptors on GABA receptor-dependent [Cl -]i changes over a wide range of initial [Cl -]i, which gave us the opportunity to evaluate the role of ionic plasticity for mature and developing nervous systems [3,40]. In the mature brain GABAergic activity causes an increase in [Cl -]i [11,16,25,41,42], thereby decreasing the inhibitory action of the GABAergic system [13,26,27,33]. The present study demonstrates that glutamatergic co-stimulation enhances the GABAergic Cl --influx and thus enhances the activity-dependent [Cl -]i increase, as has recently been shown in-vitro [32] and insilico [33].…”

“…In the mature brain GABAergic activity causes an increase in [Cl -]i [11,16,25,41,42], thereby decreasing the inhibitory action of the GABAergic system [13,26,27,33]. The present study demonstrates that glutamatergic co-stimulation enhances the GABAergic Cl --influx and thus enhances the activity-dependent [Cl -]i increase, as has recently been shown in-vitro [32] and insilico [33]. As a consequence, the inhibitory action of GABA may be even more impaired upon a co-activation of glutamate receptors [33].…”

“…7d). These [Cl -]i changes in the individual neurites are determined by Cl --fluxes via GABAA receptors, lateral Cldiffusion within the dendritic compartment and transmembrane Cl --transport [25,29,33]. For a better quantification and display, the average [Cl -]i over all nodes of all dendrites was calculated at each simulated interval (compare e.g.…”

“…Another factor that directly influences the amount of GABAA receptor-mediated Clfluxes is a coincident membrane depolarization [11,27,31]. Accordingly, recent in-vitro and in-silico studies demonstrated that coincident glutamatergic depolarization profoundly augments the GABAA receptor mediated Clfluxes [32,33]. However, to our knowledge it has not been analyzed how the interdependency between glutamatergic and GABAergic inputs affects the magnitude and the spatiotemporal properties of activity dependent [Cl -]i changes.…”