Efficacy of Synaptic Inhibition Depends on Multiple, Dynamically Interacting Mechanisms Implicated in Chloride Homeostasis

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