Dosage sensitivity intolerance of VIPR2 microduplication is disease causative to manifest schizophrenia-like phenotypes in a novel BAC transgenic mouse model

Abstract

Recent genome-wide association studies (GWAS) have identified copy number variations (CNVs) at chromosomal locus 7q36.3 that significantly contribute to the risk of schizophrenia, with all of the microduplications occurring within a single gene: vasoactive intestinal peptide receptor 2 (VIPR2). To confirm disease causality and translate such a genetic vulnerability into mechanistic and pathophysiological insights, we have developed a series of conditional VIPR2 bacterial artificial chromosome (BAC) transgenic mouse models of VIPR2 CNV. VIPR2 CNV mouse model recapitulates gene expression and signaling deficits seen in human CNV carriers. VIPR2 microduplication in mice elicits prominent dorsal striatal dopamine dysfunction, cognitive, sensorimotor gating, and social behavioral deficits preceded by an increase of striatal cAMP/PKA signaling and the disrupted early postnatal striatal development. Genetic removal of VIPR2 transgene expression via crossing with Drd1a-Cre BAC transgenic mice rescued the dopamine D2 receptor abnormality and multiple behavioral deficits, implicating a pathogenic role of VIPR2 overexpression in dopaminoceptive neurons. Thus, our results provide further evidence to support the GWAS studies that the dosage sensitivity intolerance of VIPR2 is disease causative to manifest schizophrenia-like dopamine, cognitive, and social behavioral deficits in mice. The conditional BAC transgenesis offers a novel strategy to model CNVs with a gain-of -copies and facilitate the genetic dissection of when/where/how the genetic vulnerabilities affect development, structure, and function of neural circuits. Our findings have important implications for therapeutic development, and the etiology-relevant mouse model provides a useful preclinical platform for drug discovery.

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Acknowledgements

The project was supported by a NARSAD young investigator award from the Brain & Behavior Research Foundation and a Center for Excellence in Arthritis and Rheumatology grant from LSUHSC to X-HL. X-HL conceived the idea, designed the experiments, and wrote the manuscript. XWY provided valuable guidance in the study, assisting in interpreting the findings, and modifying the manuscript. XWY and NEG served as mentors for the NARSAD award. XT performed most of the behavioral and pathologic studies in Figs. 15 and Supplementary Figs. S2–12. BL at LSUHSC performed the HPLC experiment. AR, MWE-S, AB, IVS, and KH performed some behavioral and pathologic studies. Dr Rebecca Berdeaux from the Department of Integrative Biology and Pharmacology, McGovern Medical School at The University of Texas Health Science Center at Houston generously provided CRE-LUC knockin mice. RLK provided open filed, rotarod behavioral equipment and synaptophysin antibody.

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Tian, X., Richard, A., El-Saadi, M.W. et al. Dosage sensitivity intolerance of VIPR2 microduplication is disease causative to manifest schizophrenia-like phenotypes in a novel BAC transgenic mouse model. Mol Psychiatry 24, 1884–1901 (2019). https://doi.org/10.1038/s41380-019-0492-3

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