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.
| Original language | English (US) |
|---|---|
| Article number | 825 |
| Journal | Nature communications |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
Funding
We would like to thank Professor Nicolas Katsanis (Duke University) for providing the backcrossed 16p11.2 mice and Professor Mitsunori Fukuda (Tohoku University) for the T7-VAMP2 and STX1A mouse cDNA plasmids. Prrt2 mice were kindly provided by the University of Tennessee Health Science Center. We are very grateful to the Behavioral Phenotyping Core at Northwestern University for the use of their equipment and expertise. This work was supported by National Institute of Mental Health (NIMH) and National Institute of Neurological Disorders and Stroke (NINDS) Grants: MH097216 (to P.P.), NS108874 (to A.L.G.), NS053792 and NS084959 (to J.A.K.), R56NS094965, R03NS101485 and R56NS123059 (to M.S.L.), an Individual Biomedical Research Award from The Hartwell Foundation (J.N.S.) and a Swiss National Science Foundation Early Postdoc Mobility Fellowship (P2SKP3_161675 to M.P.F.). dup/+ +/- We would like to thank Professor Nicolas Katsanis (Duke University) for providing the backcrossed 16p11.2dup/+mice and Professor Mitsunori Fukuda (Tohoku University) for the T7-VAMP2 and STX1A mouse cDNA plasmids. Prrt2+/-mice were kindly provided by the University of Tennessee Health Science Center. We are very grateful to the Behavioral Phenotyping Core at Northwestern University for the use of their equipment and expertise. This work was supported by National Institute of Mental Health (NIMH) and National Institute of Neurological Disorders and Stroke (NINDS) Grants: MH097216 (to P.P.), NS108874 (to A.L.G.), NS053792 and NS084959 (to J.A.K.), R56NS094965, R03NS101485 and R56NS123059 (to M.S.L.), an Individual Biomedical Research Award from The Hartwell Foundation (J.N.S.) and a Swiss National Science Foundation Early Postdoc Mobility Fellowship (P2SKP3_161675 to M.P.F.).
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy