Sex Differences in Cellular and Synaptic Cerebellar Physiology, and Disrupted Cerebellar Signaling in Mouse Models for Autism Spectrum Disorder

Neurons of the cerebellar nuclei (CbN) form the sole output of the cerebellum, and integrate excitatory inputs from extracerebellar sources and inhibitory inputs from Purkinje cells of the cerebellar cortex. To understand the specific cellular and synaptic properties of cerebellar cells that allow them to perform the computations necessary to contribute to motor coordination and learning, as well as higher order cognitive functions, we have utilized mouse models of disorders in which the cerebellum is affected. Genes implicated in autism spectrum disorder (ASD) are expressed in the cerebellum, and cerebella of ASD patients often have morphological abnormalities. Here, we investigated the effects of Angelman syndrome-associated Gabrb3 mutation or the Rett syndrome-associated Mecp2 mutation on cerebellar signaling. In order to determine whether the Gabrb3 mutation has differential effects on males and females, we analyzed data from each sex separately. This revealed sex differences in cerebellar signaling in wild-type mice, as well as a sex-specific effect of the Gabrb3 mutation. CbN cells of wild-type males have differences in intrinsic and synaptic properties compared to wild-type females, and the Gabrb3 mutation affects CbN cell properties in males, but not in females. In males with a Mecp2 mutation, Purkinje cells had abnormal firing patterns and action potential waveforms indicative of distal action potential initiation. Thus, in two ASD mouse models, cerebellar signaling is disrupted, and furthermore, the effects of the ASD-linked mutation can be sex-specific.