Molecular, Synaptic, and Circuit Basis for Schizophrenia-related Phenotypes

描述（由申请人提供）：在美国和加拿大，神经精神疾病是导致疾病负担的主要原因，远远超过其他疾病，如心血管疾病和癌症（WHO统计）。由于我们缺乏与神经精神疾病的根本原因相关的基本知识，治疗神经精神疾病的进展受到严重阻碍。树突棘形态发生缺陷是由动态肌动蛋白重塑调节的过程，是这些疾病的共同特征，也与压力有关，这可能导致精神分裂症等疾病。此外，越来越清楚的是，调节兴奋性突触肌动蛋白信号的基因中断是精神分裂症、自闭症和智力残疾的危险因素。Arp2/3复合物在树突棘中富集，并刺激许多与神经精神疾病有关的基因下游分支肌动蛋白的形成。最近，我们发表了Arp2/3在小鼠中的条件性缺失导致与精神分裂症模型相关的多种突触和行为表型的逐步发展。抗精神病药物氯氮平和氟哌啶醇使许多精神分裂症相关行为正常化。这项资助的具体目的是建立在这些令人兴奋的发现的基础上，以解决sz相关表型如何在突触和电路水平上进化以及慢性应激如何影响这一基本问题。我们预计这些目标的结果将弥合我们关于sz样表型如何在体内出现的知识差距，为该疾病的预防和可能的治疗提供新的未来方向。

DESCRIPTION (provided by applicant): Neuropsychiatric disorders are the leading cause of disease burden in the United States and Canada, far outpacing other maladies such as cardiovascular disease and cancer (WHO statistics). Progress in treating neuropsychiatric disorders is severely hampered by our lack of basic knowledge related to their underlying causes. Defects in dendritic spine morphogenesis, a process regulated by dynamic actin remodeling, is a common feature of these disorders and is also associated with stress, which may precipitate disorders such as schizophrenia. Moreover, it is increasingly clear that disruptions in genes that regulate signaling to excitatory synaptic actin are risk factors for schizophrenia, autism, and intellectual disability. Arp2/3 complex is enriched in dendritic spines and stimulates the formation of branched actin downstream of many genes implicated neuropsychiatric disorders. Recently we published that the conditional loss of Arp2/3 in mice leads to the progressive development of multiple synaptic and behavioral phenotypes relevant to models of schizophrenia. Many of the schizophrenia-related behaviors are normalized by the antipsychotics clozapine and haloperidol. The specific aims of this grant build on these exciting findings to address fundamental questions of how SZ-related phenotypes evolve at the synaptic and circuit level and how this is influenced by chronic stress. We anticipate the results of these aims will bridge our knowledge gap regarding how SZ-like phenotypes emerge in vivo, leading to new future directions for the prevention and possible treatments of the disorder.