Association of Mouse Dlg4 (PSD-95) Gene Deletion and Human DLG4 Gene Variation With Phenotypes Relevant to Autism Spectrum Disorders and Williams' Syndrome

Objective: Research is increasingly linking autism spectrum disorders and other neurodevelopmental disorders to synaptic abnormalities (synaptopathies). PSD-95 (postsynaptic density-95, DLG4) orchestrates protein-protein interactions at excitatory synapses and is a major functional bridge interconnecting a neurexin-neuroligin-SHANK pathway implicated in autism spectrum disorders. Method: The authors characterized behavioral, dendritic, and molecular phenotypic abnormalities relevant to autism spectrum disorders in mice with PSD-95 deletion (Dlg4(-/-)). The data from mice led to the identification of single-nucleotide polymorphisms (SNPs) in human DLG4 and the examination of associations between these variants and neural signatures of Williams' syndrome in a normal population, using functional and structural neuroimaging. Results: Dlg4(-/-) showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses. Dlg4(-/-) had subtle dysmorphology of amygdala dendritic spines and altered forebrain expression of various synaptic genes, including Cyln2, which regulates cytoskeletal dynamics and is a candidate gene for Williams' syndrome. A significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling, both of which characterize Williams' syndrome. Conclusions: These findings demonstrate that Dlg4 gene disruption in mice produces a complex range of behavioral and molecular abnormalities relevant to autism spectrum disorders and Williams' syndrome. The study provides an initial link between human DLG4 gene variation and key neural endophenotypes of Williams' syndrome and perhaps cortico-amygdala regulation of emotional and social processes more generally.