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

doi:10.1016/j.expneurol.2023.114339

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

Exp Neurol. 2023 Apr:362:114339. doi: 10.1016/j.expneurol.2023.114339. Epub 2023 Jan 27.

Authors

Affiliations

¹ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan; Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima 734-8553, Japan. Electronic address: yukioago@hiroshima-u.ac.jp.
² Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Interdepartmental Doctoral Program, University of California Los Angeles, Los Angeles, CA 90095, USA.
³ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁵ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁶ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Psychology, Brain Research Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Staglin Center for Brain and Behavioral Health, University of California Los Angeles, Los Angeles, CA 90095, USA; Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; Department of Psychology, Brain Research Institute, University of California Los Angeles, Los Angeles, CA 90095, USA; Staglin Center for Brain and Behavioral Health, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁸ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan; Division of Bioscience, Institute for Datability Science, Osaka University, Suita, Osaka 565-0871, Japan; Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan; Department of Molecular Pharmaceutical Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
⁹ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: jwaschek@mednet.ucla.edu.

PMID: 36717013
DOI: 10.1016/j.expneurol.2023.114339

Abstract

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.

Keywords: MRI; Microencephaly; Nestin-Cre; Schizophrenia; VIPR2; VPAC2 receptor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
Humans
Male
Mice
Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism
Prepulse Inhibition
Receptors, Vasoactive Intestinal Peptide, Type II* / metabolism
Vasoactive Intestinal Peptide / chemistry
Vasoactive Intestinal Peptide / metabolism
Vasoactive Intestinal Peptide / pharmacology
White Matter* / metabolism

Substances

Receptors, Vasoactive Intestinal Peptide, Type II
Vasoactive Intestinal Peptide
Pituitary Adenylate Cyclase-Activating Polypeptide
VIPR2 protein, human
Vipr2 protein, mouse

Grants and funding

U54 HD087101/HD/NICHD NIH HHS/United States