A number of genetic mutations have been linked to an increased risk for autism spectrum disorder (ASD). Despite different genetic causes, studies of individuals with ASD and in animal models suggest that common synaptic defects may be responsible for the convergence of ASD behavioral phenotypes. Alterations in synapse density and morphology are common among cognitive disorders, including ASD and fragile X syndrome (FXS). This suggests that similar therapeutic strategies targeting these pathologies may be effective across genetically distinct forms of ASD. However, to date, few studies have assessed whether there are shared synaptic endophenotypes across the human ASD spectrum or in ASD mouse models, with molecular and functional heterogeneity complicating the existing data.

Philippe Mourrain’s lab has devised imaging and computational solutions that allow sub-synaptic analysis of molecular heterogeneity across diverse synaptic populations across entire brain regions. In a previous publication, the Mourrain group used this novel approach to assess the synaptic population impact of FXS across multiple layers in the cortex and demonstrated that this synaptic profiling could also be used to address the quantitative efficacy of drugs on the molecular endophenotypes of the disease¹. Mourrain now aims to break down the complex synaptic defects in the brains of ASD model mice into measurable endophenotypes through the comprehensive synapse profile of the prefrontal and somatosensory cortex of three mouse genetic models of ASD — 16p11.2 deletion as well as Shank3 and CNTNAP2 knockouts.

In doing so, Mourrain aims to uncover common endophenotypes at the subsynaptic and synapse population levels across genetically distinct ASD models. Furthermore, based on these common molecular endophenotypes, Mourrain’s team will evaluate the efficacy of promising drugs currently on trial for the treatment of ASD; these include bumetamide, arbaclofen, a brain vasopressin inhibitor and an mGluR5 inhibitor (CTEP). This study will greatly increase our understanding of the potential synaptic endophenotypes underlying common ASD behaviors and provide a quantitative tool for the evaluation and understanding of drug efficacy in the treatment of ASD.