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Setd5 Haploinsufficiency Alters Neuronal Network Connectivity and Leads to Autistic-like Behaviors in Mice


SETD5, a gene recently linked to intellectual disability (ID) and autism spectrum disorder (ASD) encodes a putative histone methyltransferase. To date, no causal evidence has linked SETD5 haploinsufficiency with ID/ASD, and a potential underlying mechanism of action remains unknown. Here, we characterized the impact of Setd5 on neurodevelopment using molecular, cellular, and behavioral assays in the Setd5+/- mouse. Setd5+/- animals manifest several autism-like behaviors, including hyperactivity, increased anxiety, cognitive deficits, and altered social interactions. Anatomical differences in cortex were observed in Setd5+/- adult brains, accompanied by a deficit of deep-layer cortical neurons in the early postnatal brain. Setd5+/- cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth. Development of network connectivity was impaired in Setd5+/- neurons. At the molecular level, SETD5 methylated H3K4 in a SET domain-dependent manner. Together, our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor. Thus, the Setd5+/- animal represents a novel model for ASD and yields insight into the epigenetic regulation of neurodevelopment.

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