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

• DOI: 10.1176/appi.ajp.2010.10040484
• Publication Date: 2010-10-16T00:29:29Z
• Authors: Michael Feyder; Rose-Marie Karlsson; Poonam Mathur; Matthew Lyman; Roland Bock; Reza Momenan; Jeeva Munasinghe; Maria Luisa Scattoni; Jessica Ihne; Marguerite Camp; Carolyn Graybeal; Douglas Strathdee; Alison Begg; Veronica A. Alvarez; Peter Kirsch; Marcella Rietschel; Sven Cichon; Henrik Walter; Andreas Meyer-Lin...; Seth G.N. Grant; Andrew Holmes
• Keywords: Variation (astronomy); Association (psychology)

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