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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Article number108338
JournalCell Reports
Volume33
Issue number5
DOIs
StatePublished - Nov 3 2020
Externally publishedYes

Keywords

  • GABA
  • anxiety-like behavior
  • cerebellum
  • hyperexcitability
  • maternal behavior
  • social behavior
  • stress
  • tonic inhibition

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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