Comparing synaptic proteomes across seven mouse models for autism reveals molecular subtypes and deficits in Rho GTPase signaling

Abstract

Impaired synaptic function is a common phenotype in animal models for autism spectrum disorder (ASD), and ASD risk genes are enriched for synaptic function. Here we leverage the availability of multiple ASD mouse models exhibiting synaptic deficits and behavioral correlates of ASD and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare the hippocampal synaptic proteomes from 7 mouse models. We identified common altered cellular and molecular pathways at the synapse, including changes in Rho family small GTPase signaling, suggesting that it may be a point of convergence in ASD. Comparative analyses also revealed clusters of synaptic profiles, with similarities observed among models for Fragile X syndrome (Fmr1 knockout), PTEN hamartoma tumor syndrome (Pten haploinsufficiency), and the BTBR+ model of idiopathic ASD. Opposing changes were found in models for cortical dysplasia focal epilepsy syndrome (Cntnap2 knockout), Phelan McDermid syndrome (Shank3 InsG3680), Timothy syndrome (Cacna1c G406R), and ANKS1B syndrome (Anks1b haploinsufficiency), which were similar to each other. We propose that these clusters of synaptic profiles form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Drawn from an internally controlled survey of the synaptic proteome across animal models, our findings support the notion that synaptic dysfunction in the hippocampus is a shared mechanism of disease in ASD, and that Rho GTPase signaling may be an important pathway leading to disease phenotypes in autism.

Microexon alternative splicing of small GTPase regulators: Implication in central nervous system diseases

“…Therefore, defects in GEF and/or GAP activity might lie in splicing regulatory elements, consequently causing mis‐splicing; however, direct evidence for this possibility needs further investigation. In addition to these findings, a comparison of the hippocampal synaptic proteomes of seven types of ASD mouse models unveiled common alterations in the Rho GTPase signaling pathway (Carbonell et al, 2021). In particular, Rac1 expression was significantly increased in ASD mouse models.…”

Alteration of synaptic protein composition during developmental synapse maturation

“…In Shank3‐deficient mice, the PSD of the striatum and hippocampus showed region‐dependent alteration, with downregulation of glutamate receptor and scaffolding molecules in the striatum and upregulation of voltage‐gated channel subunit in the hippocampus (Reim et al, 2017). Another recent report shows synaptic proteome analysis of seven mouse models for ASD: Fmr1 knockout, phosphatase and tensin homologue deleted on chromosome 10 ( Pten ) Het, Cntnap2 knockout, Shank3 mutant, Cacna1c mutant, Anks1b Het and BTBR (Carbonell et al, 2023). They showed an altered abundance of proteins related to the Rho GTPase signalling pathway in these mice.…”