Mild KCC2 Hypofunction Causes Inconspicuous Chloride Dysregulation that Degrades Neural Coding.

Nicolas Doyon,Yves De Koninck,Steven A Prescott

doi:10.3389/fncel.2015.00516

Abstract

Disinhibition caused by Cl− dysregulation is implicated in several neurological disorders. This form of disinhibition, which stems primarily from impaired Cl− extrusion through the co-transporter KCC2, is typically identified by a depolarizing shift in GABA reversal potential (EGABA). Here we show, using computer simulations, that intracellular [Cl−] exhibits exaggerated fluctuations during transient Cl− loads and recovers more slowly to baseline when KCC2 level is even modestly reduced. Using information theory and signal detection theory, we show that increased Cl− lability and settling time degrade neural coding. Importantly, these deleterious effects manifest after less KCC2 reduction than needed to produce the gross changes in EGABA required for detection by most experiments, which assess KCC2 function under weak Cl− load conditions. By demonstrating the existence and functional consequences of “occult” Cl− dysregulation, these results suggest that modest KCC2 hypofunction plays a greater role in neurological disorders than previously believed.

Highlights

The balance of synaptic excitation and inhibition is critical for proper neural processing (Shadlen and Newsome, 1994; Wong et al, 2000; Soto-Trevino et al, 2001; Haider et al, 2006; Buzsáki et al, 2007; Vogels and Abbott, 2009)
These results suggest that modest KCC2 hypofunction— subtle enough to go undetected by experiments that do test elevated Cl− loads—can have important consequences for neural coding
In healthy adult central neurons, Cl− influx via GABAA receptors is counterbalanced by Cl− efflux via KCC2 and the equilibrium value of [Cl−]i depends on the strength of each process

Summary

INTRODUCTION

The balance of synaptic excitation and inhibition is critical for proper neural processing (Shadlen and Newsome, 1994; Wong et al, 2000; Soto-Trevino et al, 2001; Haider et al, 2006; Buzsáki et al, 2007; Vogels and Abbott, 2009). Strong GABAergic input can cause sizeable increases in [Cl−]i (Thompson and Gahwiler, 1989; Kaila, 1994; Staley et al, 1995; Doyon et al, 2011), indicating that Cl− extrusion capacity is transiently overwhelmed. Such changes have been shown to perpetuate epileptiform activity during the clonic phase of seizures (Ellender et al, 2014) and are important for the operation of rhythmic motor networks (Viemari et al, 2011). Modest KCC2 hypofunction could have more widespread consequences than previously believed

MATERIALS AND METHODS

RESULTS

DISCUSSION