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 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. [Display omitted] •δGABAA deletion in cerebellar granule cells causes input layer hyperexcitability•Hyperexcitability leads to increased anxiety- and stress-related behaviors•Females lacking cerebellar δGABAA show deficits in social and maternal behavior•Hyperactivation of granule cells during stress alters activity in many brain regions Rudolph et al. show that deletion of the neuromodulator and hormone-sensitive δGABAA receptor subunit from cerebellar granule cells results in anxiety-like behaviors and female-specific deficits in social behavior and maternal care. δGABAA deletion is associated with hyperexcitability of the cerebellar input layer and altered activation of many stress-related brain regions.