Ago Yukio, Van Christina, Condro Michael C, Hrncir Haley, Diep Anna L, Rajbhandari Abha K, Fanselow Michael S, Hashimoto Hitoshi, MacKenzie-Graham Allan J, Waschek James A
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.
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.
Exp Neurol. 2023 Apr;362:114339. doi: 10.1016/j.expneurol.2023.114339. Epub 2023 Jan 27.
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.
针对欧洲和汉族人群开展的大规模研究发现，编码VPAC2（一种能与血管活性肠肽和垂体腺苷酸环化酶激活多肽高亲和力结合的受体）的VIPR2基因存在一系列罕见的功能获得性微重复，这些微重复与精神分裂症风险升高达13倍相关。为了探究VPAC2受体过度激活如何影响大脑发育，我们使用了一种特征明确的Nestin-Cre小鼠品系，并采用敲入方法在中枢神经系统中过表达人VPAC2。结果发现，过表达VPAC2的小鼠脑重量显著降低。磁共振成像分析证实脑尺寸减小，海马灰质体积特异性减小，而全脑白质体积却出现反常增加。在过表达VPAC2的小鼠中观察到了行为上的性别特异性变化，如前脉冲抑制受损和情境恐惧记忆受损。这些数据表明，VPAC2受体可能在脑形态发生中起关键作用，并提示发育过程中VPAC2信号过度激活在某些形式的精神分裂症中起机制性作用。
