Ago Yukio, Condro Michael C, Tan Yossan-Var, Ghiani Cristina A, Colwell Christopher S, Cushman Jesse D, Fanselow Michael S, Hashimoto Hitoshi, 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, 635 Charles E. Young Drive South, Los Angeles, CA, 90095, USA.
Psychopharmacology (Berl). 2015 Jun;232(12):2181-9. doi: 10.1007/s00213-014-3848-z. Epub 2015 Jan 11.
An abundance of genetic and epidemiologic evidence as well as longitudinal neuroimaging data point to developmental origins for schizophrenia and other mental health disorders. Recent clinical studies indicate that microduplications of VIPR2, encoding the vasoactive intestinal peptide (VIP) receptor VPAC2, confer significant risk for schizophrenia and autism spectrum disorder. Lymphocytes from patients with these mutations exhibited higher VIPR2 gene expression and VIP responsiveness (cAMP induction), but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown.
We subcutaneously administered the highly selective VPAC2 receptor agonist Ro 25-1553 to C57BL/6 mice from postnatal day 1 (P1) to P14 to determine if overactivation of VPAC2 receptor signaling during postnatal brain maturation affects synaptogenesis and selected behaviors.
Western blot analyses on P21 revealed significant reductions of synaptophysin and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex, but not in the hippocampus in Ro 25-1553-treated mice. The same postnatally restricted treatment resulted in a disruption in prepulse inhibition of the acoustic startle measured in adult mice. No effects were observed in open-field locomotor activity, sociability in the three-chamber social interaction test, or fear conditioning or extinction.
Overactivation of the VPAC2 receptor in the postnatal mouse results in a reduction in synaptic proteins in the prefrontal cortex and selective alterations in prepulse inhibition. These findings suggest that the VIPR2-linkage to mental health disorders may be due in part to overactive VPAC2 receptor signaling during a critical time of synaptic maturation.
大量的遗传和流行病学证据以及纵向神经影像学数据表明，精神分裂症和其他心理健康障碍具有发育起源。最近的临床研究表明，编码血管活性肠肽（VIP）受体VPAC2的VIPR2基因微重复会显著增加患精神分裂症和自闭症谱系障碍的风险。这些突变患者的淋巴细胞表现出更高的VIPR2基因表达和VIP反应性（cAMP诱导），但VPAC2信号过度活跃可能导致这些精神疾病的机制尚不清楚。
我们从出生后第1天（P1）至P14对C57BL/6小鼠皮下注射高选择性VPAC2受体激动剂Ro 25-1553，以确定出生后脑成熟过程中VPAC2受体信号的过度激活是否会影响突触形成和特定行为。
对P21小鼠进行的蛋白质免疫印迹分析显示，Ro 25-1553处理的小鼠前额叶皮质中突触素和突触后致密蛋白95（PSD-95）显著减少，但海马体中没有。同样在出生后进行的有限治疗导致成年小鼠听觉惊吓前脉冲抑制受到破坏。在旷场运动活动、三室社交互动试验中的社交能力、恐惧条件反射或消退方面未观察到影响。
出生后小鼠VPAC2受体的过度激活导致前额叶皮质中突触蛋白减少，并在前脉冲抑制方面产生选择性改变。这些发现表明，VIPR2与精神健康障碍的关联可能部分归因于突触成熟关键时期VPAC2受体信号的过度活跃。
