Psychosis-related Physiological and Neuronal Phenotypes in 22q11 Deletion Syndrome

项目摘要 在这项修订后的提案中，我们计划检查大脑皮质神经元的生理和突触特性。 多能干细胞(IPSC)来源的神经元以及精神分裂症(SCZ)相关 生理表型，收集自22q11缺失综合征(22q11DS)患者。 这种综合征与患精神分裂症的风险增加20-30倍有关。20%-30% 患有22q11DS的患者在成年早期发展为SCZ。声学惊吓反应(ASR)是 这是一种进化上保守的反射，与健康对照组相比，SCZ的某些方面有所不同。 根据表型对非22q11DS高危人群进行的SCZ研究 这些特征(即有前驱症状的特征)表明ASR的潜伏期可以预测 转换为SCZ。失配负波(MMN)是一种对异常或异常反应的诱发电位 “奇怪的”声刺激嵌入在一系列重复的声刺激中。受损的 产生对奇怪刺激的增强反应的是良好复制的MMN 在SCZ中看到异常。我们建议的工作将检查老年人的ASR措施和MMN 有22q11DS的青少年和年轻人(和健康对照组)来检验这一假设 ASR和/或MMN的潜伏期将预测前驱症状的严重程度，并最终 在这个基因定义的高危人群中，转换为SCZ。同时我们也会研究 22q11DS来源的IPSC来源神经元ASR和MMN的潜在细胞机制 患者在ASR中表现出极端的潜伏期惊厥。我们假设这样做 将确定22q11表型影响的潜在细胞机制 缺失(包括SCZ的风险增加)。因此，这项研究将阐明基因是如何 机制改变了与观察到的临床和生理差异相关的细胞特性 在SCZ和SCZ前驱。

Project Summary In this revised proposal, we plan to examine the physiological and synaptic properties of pluripotent stem cell (iPSC)-derived neurons, as well as schizophrenia (SCZ)-related physiological phenotypes, gathered from patients with 22q11 Deletion Syndrome (22q11DS). The syndrome associates with a 20-30 fold increase in the risk for schizophrenia. 20-30% of patients with 22q11DS develop SCZ by early adulthood. The acoustic startle response (ASR) is an evolutionarily conserved reflex, aspects of which differ in SCZ compared to healthy controls. Prior work on non-22q11DS individuals at high risk for SCZ based on their phenotypic characteristics (i.e., those with prodromal symptoms) suggest that the latency of ASR predicts conversion to SCZ. Mismatch negativity (MMN) is an evoked potential in response to unusual or “oddball” acoustic stimuli imbedded within a train of repetitive acoustic stimuli. Impaired generation of an enhanced response to the oddball stimuli is the well-replicated MMN abnormality seen in SCZ. Our proposed work will examine ASR measures and MMN in older adolescents and young adults with 22q11DS (and healthy controls) to test the hypothesis that latency of the ASR and/or MMN will predict severity of prodromal symptoms, and ultimately conversion to SCZ, in this genetically defined high-risk group. Simultaneously we will study potential cellular mechanisms related to ASR and MMN in iPSC-derived neurons from 22q11DS patients exhibiting extreme values of latency to startle in the ASR. We hypothesize that doing so will identify potential cellular mechanisms underlying the phenotypic impact of the 22q11 deletion (including elevated risk for SCZ). This research will thus shed light on how genetic mechanisms alter cellular properties relevant to clinical and physiological differences observed in SCZ and the SCZ prodrome.