Molecular mechanisms of abnormal dendritic spine plasticity in schizophrenia

描述（由申请人提供）：多种证据支持异常突触连通性在精神分裂症中起关键作用，但其发病机制的分子机制尚不清楚。了解这些机制可能使我们能够确定治疗干预的新目标，特别是在疾病过程的早期。该应用将集中于树突棘作为大脑连接的细胞基质，因为大多数兴奋性突触位于棘上，并且在精神分裂症中脊椎密度降低已被广泛记录。越来越多的证据表明，已知的精神分裂症易感基因调节脊柱，脊柱可塑性的调节因子与精神分裂症有关，这有力地支持了脊柱可塑性分子网络的扰动在精神分裂症发病机制中起关键作用的模型。然而，该网络中的遗传改变构成与精神分裂症相关的特定神经生物学表型的机制尚不清楚。最近的数据表明，罕见的变异（包括氨基酸突变）累积起来占精神分裂症“缺失遗传性”的很大一部分，并聚集在控制突触的基因网络中。据估计，这类突变中的很大一部分会损害蛋白质功能，因此许多突变预计会导致大脑回路的改变。因此，我们提出，通过鉴定、检测关联和表征精神分裂症中富集的罕见变异，我们将为疾病发病机制提供重要的新见解，因为这些突变提供了有关受影响的分子和细胞功能的详细知识。根据我们的初步数据，我们假设控制树突脊柱可塑性的基因中罕见的编码变异，在精神分裂症患者中积累丰富，破坏皮层连通性并影响携带者的神经形态学和认知测量。采用多学科转化方法，结合细胞模型中的人类遗传学、分子和电生理学研究、小鼠功能验证以及患者的认知评估和脑结构成像，我们将追求以下具体目标：1)评估精神分裂症患者脊柱可塑性基因突变对细胞的影响。2)确定脊柱可塑性基因突变对谷氨酸突触传递的影响。3)探讨脊柱可塑性基因突变对小鼠皮质超微结构和功能连接的影响。4)评估脊柱可塑性基因突变与患者表型指标的关系。

DESCRIPTION (provided by applicant): Multiple lines of evidence support a key role for abnormal synaptic connectivity in schizophrenia, but the molecular mechanisms underlying its pathogenesis are not known. Understanding these mechanisms may allow us to identify new targets for therapeutic intervention, especially early in the course of illness. The application wil focus on dendritic spines as cellular substrates of brain connectivity, because the majority of excitatory synapses are located on spines, and reduced spine density has been extensively documented in schizophrenia. Mounting evidence indicating that known schizophrenia susceptibility genes regulate spines and that regulators of spine plasticity are implicated in schizophrenia, strongly support the model that perturbations in the molecular network underlying spine plasticity are critically involved in the pathogenesis of schizophrenia. However, the mechanisms through which genetic alterations in this network underlie specific neurobiological phenotypes related to schizophrenia are not known. Recent data indicates that rare variants (including amino acid mutations) cumulatively account for a significant fraction of the "missing heritability" in schizophrenia, and cluster in gene networks that control synapses. Because a large fraction of such mutations are estimated to impair protein function, many are expected to cause brain circuit alterations. Thus, we propose that by identifying, testing for association, and characterizing rare variants enriched in schizophrenia, we will provide critical new insights into disease pathogenesis, because such mutations provide detailed knowledge about the affected molecular and cellular functions. Based on our preliminary data, we hypothesize that rare coding variants in genes that control dendritic spine plasticity, cumulativel enriched in subjects with schizophrenia, disrupt cortical connectivity and impact neuromorphological and cognitive measures in carriers. Using a multidisciplinary translational approach that combines human genetics, molecular and electrophysiological studies in cellular models, functional validation in mice, and cognitive assessment and structural brain imaging in patients, we will pursue these specific aims: 1) To assess the cellular impact of mutations in spine plasticity genes identified in schizophrenia subjects. 2) To determine the impact of mutations in spine plasticity genes on glutamatergic synaptic transmission. 3) To determine the impact of mutations in spine plasticity genes on cortical ultrastructure and functional connectivit in mice. 4) To assess the relationships between mutations in spine plasticity genes and phenotypic measures in patients.