Sex differences in cerebellar synaptic transmission and sex-specific responses to autism-linked Gabrb3 mutations in mice

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Abstract

Neurons of the cerebellar nuclei (CbN) transmit cerebellar signals to premotor areas. The cerebellum expresses several autism-linked genes, including Gabrb3, which encodes GABA_A 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.

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Audrey A Mercer

Northwestern University Interdepartmental Neuroscience Program, Northwestern University, Evanston, United States

Competing interests
No competing interests declared.
Kristin J Palarz

Department of Neurbiology, Northwestern University, Evanston, United States

Competing interests
No competing interests declared.
Nino Tabatadze

Department of Neurobiology, Northwestern University, Evanston, United States

Competing interests
No competing interests declared.
Catherine S Woolley

Department of Neurobiology, Northwestern University, Evanston, United States

Competing interests
No competing interests declared.
Indira M Raman

Department of Neurobiology, Northwestern University, Evanston, United States

For correspondence
i-raman@northwestern.edu

Competing interests
Indira M Raman, Reviewing editor, eLife.

Ethics

Animal experimentation: All procedures conformed to institutional guidelines and were approved by the Institutional Animal Care and Use Committee of Northwestern University (Animal Welfare Assurance Number, A3283-01; IACUC Study #IS00000242).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.