Maturation of GABAergic Transmission in Cerebellar Purkinje Cells Is Sex Dependent and Altered in the Valproate Model of Autism

Yehezkel Ben-Ari,Bernard Poulain,Sébastien Roux,Ann Lohof,Jean-Louis Bossu

doi:10.3389/fncel.2018.00232

Abstract

Brain development is accompanied by a shift in gamma-aminobutyric acid (GABA) response from depolarizing-excitatory to hyperpolarizing-inhibitory, due to a reduction of intracellular chloride concentration. This sequence is delayed in Autism Spectrum Disorders (ASD). We now report a similar alteration of this shift in the cerebellum, a structure implicated in ASD. Using single GABAA receptor channel recordings in cerebellar Purkinje cells (PCs), we found two conductance levels (18 and 10 pS), the former being dominant in newborns and the latter in young-adults. This conductance shift and the depolarizing/excitatory to hyperpolarizing/inhibitory GABA shift occurred 4 days later in females than males. Our data support a sex-dependent developmental shift of GABA conductance and chloride gradient, leading to different developmental timing in males and females. Because these developmental sequences are altered in ASD, this study further stresses the importance of developmental timing in pathological neurodevelopment.

Highlights

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system
If the intracellular chloride concentration is high enough that the equilibrium potential for chloride is positive compared to the resting membrane potential, GABAA receptor activation can depolarize the cell above the action potential threshold, acting like an excitatory neurotransmitter (Ben-Ari et al, 1989; Ben-Ari, 2014)
We analyzed currents activated by isoguvacine or muscimol, two GABAA receptor agonists, recorded from 108 cell-attached patches from Purkinje cells (PCs) in acute cerebellar slices from male and female mice, between postnatal days 5 (P5) and P45

Summary

Introduction

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. If the intracellular chloride concentration is high enough that the equilibrium potential for chloride is positive compared to the resting membrane potential, GABAA receptor activation can depolarize the cell above the action potential threshold, acting like an excitatory neurotransmitter (Ben-Ari et al, 1989; Ben-Ari, 2014) This regulation of (Cl−)I has been reported in a wide range of animal species and brain structures; it is affected by many factors including sex steroids, BDNF and IGF-1 signaling (Galanopoulou, 2008; Tsutsui et al, 2011; Waddell and McCarthy, 2012; Ben-Ari, 2014; Watanabe and Fukuda, 2015).

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