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

Abstract

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.

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

“…Some proposed explanations include abnormal perception of safeness or incapability to interpret danger cues in the mutant mice (23). It is worth noting that the results we obtained for anxiety and social measurements from untreated Mecp2 mutant mice are very similar to those obtained in a PSD95 mutant mouse model, emphasizing the convergence of signaling pathways and synaptic molecules necessary for these behavioral functions (47). Indeed, IGF1 treatment improves excitatory synaptic transmission and motor behaviors in Shank3 haploinsufficient mice (48), and IGF1 application corrects synaptic transmission deficits in iPSC-derived neurons from 22q13 deletion syndrome patients (49), both of which can be attributed to enhanced PSD95 function.…”

Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species

“…greater control of environmental and genetic background (e.g., in rodents) while enabling rapid translational discovery by leveraging conserved elements of neural and behavioral systems to identify genotype-phenotype relationships (19,(36)(37)(38). By integrating a developmentally informed approach with parallel rodent and human studies (Fig.…”

Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients

“…It is plausible that JNK3 also regulates SAP102 and SHANK3, as well as numerous other as yet unknown neuronal JNK3 substrates. Importantly, mutations in both SAP102 (Tarpey et al 2004) and SHANK3 (Durand et al 2007) are associated with neurodevelopmental phenotypes in patients, and links between PSD-95 and cognitive function have been observed in studies on both probands and mouse models (Feyder et al 2010); clearly, defective regulation of these synaptic proteins could have detrimental developmental consequences.…”