Xiao Mei-Fang, Roh Seung-Eon, Zhou Jiechao, Chien Chun-Che, Lucey Brendan P, Craig Michael T, Hayes Lindsay N, Coughlin Jennifer M, Leweke F Markus, Jia Min, Xu Desheng, Zhou Weiqiang, Conover Talbot C, Arnold Don B, Staley Melissa, Jiang Cindy, Reti Irving M, Sawa Akira, Pelkey Kenneth A, McBain Chris J, Savonenko Alena, Worley Paul F
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Sci Adv. 2021 Nov 26;7(48):eabf6935. doi: 10.1126/sciadv.abf6935. Epub 2021 Nov 24.
Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset schizophrenia. NPTX2 plays an essential role in maintaining excitatory homeostasis by adaptively enhancing circuit inhibition. NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses and is coupled to circadian behavior. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. Modeling NPTX2 loss of function results in failure of parvalbumin interneurons in their adaptive contribution to behavioral stress, and animals exhibit multiple neuropsychiatric domains. Because the genetics of schizophrenia encompasses diverse proteins that contribute to excitatory synapse plasticity, the identified vulnerability of NPTX2 function can provide a framework for assessing the impact of genetics and the intersection with stress.
精神分裂症是一种多基因疾病，其临床发病通常与行为应激有关。在此，我们基于观察结果提出了一种疾病发病机制模型，即近期发病的精神分裂症患者脑脊液中突触即刻早期基因NPTX2水平降低。NPTX2通过适应性增强回路抑制在维持兴奋性稳态中起关键作用。NPTX2的功能需要活性依赖的胞吐作用和突触处的动态脱落，并与昼夜节律行为相关。破坏兴奋性神经元特定活性依赖可塑性机制的突变会消除与行为相关的NPTX2转运。模拟NPTX2功能丧失会导致小白蛋白中间神经元无法对行为应激做出适应性贡献，且动物会表现出多个神经精神领域的问题。由于精神分裂症的遗传学涉及多种有助于兴奋性突触可塑性的蛋白质，因此所确定的NPTX2功能脆弱性可为评估遗传学影响以及与应激的交叉作用提供一个框架。
