Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior

Stephanie Rudolph,Chong Guo,Stan L Pashkovski,Tomas Osorno,Winthrop F Gillis,Jeremy M Krauss,Hajnalka Nyitrai,Isabella Flaquer,Mahmoud El-Rifai,Sandeep Robert Datta,Wade G Regehr

doi:10.1016/j.celrep.2020.108338

Abstract

SUMMARYGranule cells (GCs) of the cerebellar input layer express high-affinity δ GABAA subunit-containing GABAA receptors (δGABAARs) that respond to ambient GABA levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of δGABAA (cerebellar [cb] δ knockout [KO]) decreases tonic inhibition, makes GCs hyperexcitable, and in turn, leads to differential activation of cb output regions as well as many cortical and subcortical brain areas involved in cognition, anxiety-like behaviors, and the stress response. Cb δ KO mice display deficits in many behaviors, but motor function is normal. Strikingly, δGABAA deletion alters maternal behavior as well as spontaneous, stress-related, and social behaviors specifically in females. Our findings establish that δGABAARs enable the cerebellum to control diverse behaviors not previously associated with the cerebellum in a sex-dependent manner. These insights may contribute to a better understanding of the mechanisms that underlie behavioral abnormalities in psychiatric and neurodevelopmental disorders that display a gender bias.

Highlights

Normal brain function requires GABAergic inhibition (Ferguson and Gao, 2018; Wood et al, 2017)
We found that Granule cells (GCs)-selective deletion of dGABAA resulted in differential activation of many cortical and subcortical brain areas involved in cognition, anxiety-like behaviors, and the stress response
We first determined the overlap of Cre expression in the Gabra6Cre mouse line and dGABAA using fluorescence in situ hybridization (FISH) in whole-brain sagittal sections of Gabra6-Cre 3 flox tdTomato mice (Ai14 reporter line; Figure 1A, left panels)

Summary

Introduction

Normal brain function requires GABAergic inhibition (Ferguson and Gao, 2018; Wood et al, 2017). Tonic inhibition is mediated by GABAA receptors containing dGABAA subunits (dGABAARs), which are high affinity, slowly desensitizing, extrasynaptically located, and sensitive to fluctuations in ambient GABA levels and neuromodulators (Farrant and Nusser, 2005; Glykys et al, 2008; Martenson et al, 2017; Mihalek et al, 1999; Spigelman et al, 2003; Stell and Mody, 2002; Stell et al, 2003; Vicini et al, 2002; Wei et al, 2003).

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Discussion

Conclusion