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

Granule cells (GCs) of the cerebellar input layer express high-affinity delta GABA(A) subunit-containing GABA(A) receptors (delta GABA(A)Rs) that respond to ambient GAB(A) levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of delta GABA(A) (cerebellar [cb] delta 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 delta KO mice display deficits in many behaviors, but motor function is normal. Strikingly, delta GABA(A) deletion alters maternal behavior as well as spontaneous, stress-related, and social behaviors specifically in females. Our findings establish that delta GABA(A)Rs 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.