Overexpression of VIPR2 in mice results in microencephaly with paradoxical increased white matter volume

Yukio Ago, Christina Van, Michael C. Condro, Haley Hrncir, Anna L. Diep, Abha K. Rajbhandari, Michael S. Fanselow, Hitoshi Hashimoto, Allan J. MacKenzie-Graham, James A. Waschek

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Large scale studies in populations of European and Han Chinese ancestry found a series of rare gain-of-function microduplications in VIPR2, encoding VPAC2, a receptor that binds vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide with high affinity, that were associated with an up to 13-fold increased risk for schizophrenia. To address how VPAC2 receptor overactivity might affect brain development, we used a well-characterized Nestin-Cre mouse strain and a knock-in approach to overexpress human VPAC2 in the central nervous system. Mice that overexpressed VPAC2 were found to exhibit a significant reduction in brain weight. Magnetic resonance imaging analysis confirmed a decrease in brain size, a specific reduction in the hippocampus grey matter volume and a paradoxical increase in whole-brain white matter volume. Sex-specific changes in behavior such as impaired prepulse inhibition and contextual fear memory were observed in VPAC2 overexpressing mice. The data indicate that the VPAC2 receptor may play a critical role in brain morphogenesis and suggest that overactive VPAC2 signaling during development plays a mechanistic role in some forms of schizophrenia.

Original languageEnglish
Article number114339
JournalExperimental Neurology
StatePublished - Apr 2023


  • MRI
  • Microencephaly
  • Nestin-Cre
  • Schizophrenia
  • VIPR2
  • VPAC2 receptor


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