title: Sex differences in cerebellar synaptic transmission and sex-specific responses to autism-linked Gabrb3 mutations in mice.
abstract: Neurons of the cerebellar nuclei (CbN) transmit cerebellar signals to premotor areas. The cerebellum expresses several autism-linked genes, including GABRB3, which encodes GABAA receptor β3 subunits and is among the maternal alleles deleted in Angelman syndrome. We tested how this Gabrb3 m-/p+ mutation affects CbN physiology in mice, separating responses of males and females. Wild-type mice showed sex differences in synaptic excitation, inhibition, and intrinsic properties. Relative to females, CbN cells of males had smaller synaptically evoked mGluR1/5-dependent currents, slower Purkinje-mediated IPSCs, and lower spontaneous firing rates, but rotarod performances were indistinguishable. In mutant CbN cells, IPSC kinetics were unchanged, but mutant males, unlike females, showed enlarged mGluR1/5 responses and accelerated spontaneous firing. These changes appear compensatory, since mutant males but not females performed indistinguishably from wild-type siblings on the rotarod task. Thus, sex differences in cerebellar physiology produce similar behavioral output, but provide distinct baselines for responses to mutations.
authors.affiliation: Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Evanston, United States.|Department of Neurobiology, Northwestern University, Evanston, United States.
authors.forename: Audrey A
authors.initials: AA
authors.lastname: Mercer
authors.affiliation: Department of Neurobiology, Northwestern University, Evanston, United States.|Integrated Science Program, Northwestern University, Evanston, United States.
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Palarz
authors.affiliation: Department of Neurobiology, Northwestern University, Evanston, United States.
authors.forename: Nino
authors.initials: N
authors.lastname: Tabatadze
authors.affiliation: Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Evanston, United States.|Department of Neurobiology, Northwestern University, Evanston, United States.
authors.forename: Catherine S
authors.identifier: 0000-0002-8069-2646
authors.initials: CS
authors.lastname: Woolley
authors.affiliation: Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Evanston, United States.|Department of Neurobiology, Northwestern University, Evanston, United States.|Integrated Science Program, Northwestern University, Evanston, United States.
authors.forename: Indira M
authors.identifier: 0000-0001-5245-8177
authors.initials: IM
authors.lastname: Raman
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology*; D002531:Cerebellum / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D009154:Mutation; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D012737:Sex Factors; D009435:Synaptic Transmission
chemical_list: C546270:Gabrb3 protein, mouse; D011963:Receptors, GABA-A; D017981:Receptors, Neurotransmitter; C069474:glutamine receptor
keywords: Angelman syndrome; Purkinje; cerebellar nuclei; group I mGluR; metabotropic glutamate receptor; mouse; neuroscience; sexual dimorphism