Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub

Abstract

Neuropsychiatric disorders (NPDs) are frequently co-morbid with epilepsy, but the biological basis of shared risk remains poorly understood. The 16p11.2 duplication is a copy number variant that confers risk for diverse NPDs including autism spectrum disorder, schizophrenia, intellectual disability and epilepsy. We used a mouse model of the 16p11.2 duplication (16p11.2dup/+) to uncover molecular and circuit properties associated with this broad phenotypic spectrum, and examined genes within the locus capable of phenotype reversal. Quantitative proteomics revealed alterations to synaptic networks and products of NPD risk genes. We identified an epilepsy-associated subnetwork that was dysregulated in 16p11.2dup/+ mice and altered in brain tissue from individuals with NPDs. Cortical circuits from 16p11.2dup/+ mice exhibited hypersynchronous activity and enhanced network glutamate release, which increased susceptibility to seizures. Using gene co-expression and interactome analysis, we show that PRRT2 is a major hub in the epilepsy subnetwork. Remarkably, correcting Prrt2 copy number rescued aberrant circuit properties, seizure susceptibility and social deficits in 16p11.2dup/+ mice. We show that proteomics and network biology can identify important disease hubs in multigenic disorders, and reveal mechanisms relevant to the complex symptomatology of 16p11.2 duplication carriers.

Early developmental deletion of forebrain Ank2 causes seizure-related phenotypes by reshaping the synaptic proteome

“…The increase in synchrony is similar to another mouse model of NDDs we recently investigated, which is also associated with seizure phenotypes. 20 These activity changes could reflect increased synaptic structural connectivity, activity, or intrinsic excitability. The synchronous firing also increases with synapse density.…”

Genome-wide CNV analysis uncovers novel pathogenic regions in cohort of five multiplex families with neurodevelopmental disorders

“…Her CNV analysis pathogenic microduplication of 0.99 Mb on 16p11.2(31.871,490–32,862,089) harbouring many genes including ZNF267 and TP53TG3 . Duplication of 16p11.2 locus increase the function of neuron connectivity in the brain by upregulating the gene expression [ 30 ]. Familial background of 16p11.2 syndrome lowers the cognitive capabilities and social skills in the probands showing deleterious effects of these duplications with variable phenotypes [ 31 ].…”

Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes

“…Mutations in PPRT2 have been associated with paroxysmal movement disorders ( Heron and Dibbens, 2013 ), benign infantile familial seizures and autistic developmental regression ( Zhang et al, 2024 ), as well ataxia and seizures in 16p11.2 DEL patients ( Vlaskamp et al, 2019 ; Padmanabha et al, 2024 ). Importantly, correction of PRTT2 copy number in 16p11.2 DUP mice could rescue hypersynchronous activity and enhanced glutamate release in cortical circuits, seizure susceptibility and social deficits ( Forrest et al, 2023 ).…”