Abstract

Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABAA receptors (GABAARs). The impact of changes in steady state Cl− gradient is relatively straightforward to understand, but how dynamic interplay between Cl− influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl− load on a fast time scale, whereas Cl−extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl− gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABAAR-mediated inhibition, but increasing GABAAR input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl−. Furthermore, if spiking persisted despite the presence of GABAAR input, Cl− accumulation became accelerated because of the large Cl− driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl− and pH regulation. Several model predictions were tested and confirmed by [Cl−]i imaging experiments. Our study has thus uncovered how Cl− regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K− accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention.

Highlights

  • In the central nervous system, fast inhibition is mediated by GABAA and glycine receptor-gated Cl2 channels (GABAAR and GlyR)

  • Past experiments have established that Cl2 extrusion via KCC2 plays a crucial role in maintaining the values of ECl and EGABA below the resting membrane potential [20], but they have not established how KCC2 activity relates quantitatively to ECl and EGABA, in particular under conditions of ongoing, distributed synaptic input

  • EGABA was less negative than ECl, especially at high values of KCC2 activity, consistent with EGABA depending jointly on [Cl2]i and [HCO32]i [24]

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Summary

Introduction

In the central nervous system, fast inhibition is mediated by GABAA and glycine receptor-gated Cl2 channels (GABAAR and GlyR). Influx of Cl2 through these channels produces outward currents that cause hyperpolarization or prevent depolarization caused by concurrent excitatory input (i.e. shunting) [1,2]. Hyperpolarization and shunting both typically reduce neuronal spiking. Cl2 influx through GABAAR necessarily increases [Cl2]i, which in turn causes depolarizing shifts in the Cl2 reversal potential (ECl) [3,4]. As the Cl2 gradient is depleted and ECl rises, the efficacy of GABAAR-mediated control of spiking is compromised [5]. Mechanisms that restore the transmembrane Cl2 gradient are crucial for maintaining the efficacy of GABAAR-mediated inhibition

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