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.DOI: http://dx.doi.org/10.7554/eLife.07596.001

Targeting potassium channels to treat cerebellar ataxia

“…[1][2][3]31,32 For dendritic calcium spike experiments, slices were prepared in prewarmed (33°C) aCSF. Slice preparation at 33°C for Purkinje neuron recordings has been performed previously 33,34 and results in better preservation of dendritic morphology in our studies. Slices were prepared using a vibratome (Leica) to 300 lmol/L thickness.…”

Functional properties, topological organization and sexual dimorphism of claustrum neurons projecting to anterior cingulate cortex

“…(B) Total number of recorded cells divided according to their prevalence along the anterior-posterior axis. Recorded cells were divided into three topological locations within the claustrum: anterior (slice numbers [38][39][40][41][42], middle (slice numbers [43][44][45][46][47] and posterior (slice numbers [48][49][50][51][52]. Each location was 500 μm thick and corresponded to the Allen Institute reference mouse brain atlas (n = 22, number of cells = 115).…”

“…We found differences in the representation of SA3 and SA4 projection neurons in the anterior claustrum of males and females, indicating sexual dimorphism in the distribution of cell types within the claustrum. Sexual dimorphism is a key feature of brain organization: structural differences have been found for the dendritic spines of ACC cells [47,48], differences have been observed in the physiological properties of deep cerebellar nuclei cells [49], functional differences have been shown in circuit activity of oxytocin interneurons [46], differences in circuit responses to social environment have been seen [50] and there are sex-related differences in insular activity during sexual arousal [51][52][53][54][55][56][57]. However, to the best of our knowledge, there has been no previous report of sexual dimorphism in the claustrum.…”

Cerebellum-specific deletion of the GABAAreceptor δ subunit alters anxiety-like, social and maternal behaviors without affecting motor performance

“…Finally, protein deletion can affect gene expression in a sex-dependent manner, as occurs in Angelman syndrome (Koyavski et al, 2019). Sex differences in functional compensation have been observed in the cerebellum, as in an ASD mouse model at the level of the DCN, the first output targets of the cerebellar cortex (Mercer et al, 2016).…”