@article{2368a754348c4b01bd46fe0286ed84b0,
title = "Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior",
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.",
keywords = "GABA, anxiety-like behavior, cerebellum, hyperexcitability, maternal behavior, social behavior, stress, tonic inhibition",
author = "Stephanie Rudolph and Chong Guo and Pashkovski, {Stan L.} and Tomas Osorno and Gillis, {Winthrop F.} and Krauss, {Jeremy M.} and Hajnalka Nyitrai and Isabella Flaquer and Mahmoud El-Rifai and Datta, {Sandeep Robert} and Regehr, {Wade G.}",
note = "Funding Information: We thank Kimberly McDaniels, Michelle Ocana (Neurobiology Imaging Facility), and the animal care facility staff for supporting this project throughout. We would also like to thank Jamie Maguire for providing the flox Gabrd mice and Christopher Chen for support with the behavior data analysis. This work was supported by the NIH (R35 NS097284 to W.G.R. and NS072030 to the Neurobiology Imaging Facility). S.R. and W.G.R. conceived the project. S.R. performed electrophysiology recordings, immunohistochemistry (with help from I.F.), in situ hybridization (with help from M.E.-R.), imaging and associated analyses, behavioral testing (with help from J.M.K.), and stress experiments. C.G. performed gait analysis and eyeblink conditioning and associated analyses and prepared Figure 3. S.L.P. performed MoSeq analysis with help from W.F.G. and S.R.D. H.N. performed western blots with help from S.R. T.O. helped with data analysis. T.O. and S.L.P. prepared Figures S5 and S6. S.R. prepared all figures other than Figures 3 and S5. S.R. and W.G.R wrote the manuscript with comments from all authors. S.R.D. is on the scientific advisory board of RBNC Inc. which has licensed the MoSeq technology, and holds patents related to the use of MoSeq to characterize behavior for drug development. Funding Information: We thank Kimberly McDaniels, Michelle Ocana (Neurobiology Imaging Facility), and the animal care facility staff for supporting this project throughout. We would also like to thank Jamie Maguire for providing the flox Gabrd mice and Christopher Chen for support with the behavior data analysis. This work was supported by the NIH ( R35 NS097284 to W.G.R. and NS072030 to the Neurobiology Imaging Facility). Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = nov,
day = "3",
doi = "10.1016/j.celrep.2020.108338",
language = "English (US)",
volume = "33",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}