Towards understanding cellular mechanisms of positive symptoms of schizophrenia

描述（由申请人提供）：精神分裂症（SCZ）是一种毁灭性疾病，影响约1%的世界人口，其特征是一系列症状，包括幻觉和妄想（阳性症状）、反社会行为和迟钝的情绪（阴性症状）、工作记忆、执行功能、学习和记忆缺陷（认知症状）。这些症状背后的机制仍然未知，主要是由于缺乏有效的实验方法来模拟这种疾病。22q11.2缺失综合征（22q11DS），也被称为心面疾速综合征或DiGeorge综合征，是人类最常见的微缺失综合征。大约30%的22q11DS患者在青春期或成年早期出现SCZ。通过复制工作记忆、学习记忆和其他症状的缺陷，已经构建并验证了22q11DS小鼠模型。利用这些突变小鼠，我们和其他人已经确定了22q11DS认知症状的细胞和分子机制。然而，自我报告的症状，如幻觉，不能令人信服地在老鼠身上建立模型。在这个应用中，我们建议测试几个最近的神经科学理论和人类成像数据的预测，这些预测认为幻觉是由于投射到感觉皮层的丘脑皮质（TC）通路的缺陷造成的。在我们的脑切片和体内初步实验中，我们发现22q11DS小鼠模型在听觉皮层TC通路的突触传递和短期可塑性方面存在重大缺陷。在本研究中，我们将使用单细胞电生理学、双光子成像、双光子谷氨酸释放、光遗传学和分子工具来确定22q11d小鼠模型TC缺陷的细胞和分子机制。使用多种可用的突变小鼠品系，这些突变小鼠携带缺失的基因簇或单个基因

DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is a devastating disease that affects approximately 1% of the world's population and is characterized by a constellation of symptoms that include hallucinations and delusions (positive symptoms), antisocial behavior and blunted emotions (negative symptoms), deficits in working memory, executive function, and learning and memory (cognitive symptoms). The mechanisms underlying these symptoms remain unknown, mostly due to the lack of valid experimental approaches to model this disease. The 22q11.2-deletion syndrome (22q11DS), also known as velocardiofacialsyndrome or DiGeorge syndrome, is the most common microdeletion syndrome in humans. SCZ arises in approximately 30% of patients with 22q11DS during their adolescence or early adulthood. Mouse models of 22q11DS have been constructed and validated by replicating deficits in working memory, learning and memory, and other symptoms. Using these mutant mice, we and others have identified cellular and molecular mechanisms underlying the cognitive symptoms of 22q11DS. However, self-reported symptoms such as hallucinations cannot be convincingly modeled in mice. In this application, we propose to test the predictions of several recent neuroscience theories and human imaging data that hallucinations result from deficiencies in thalamocortical (TC) pathways that project to the sensory cortices. In our preliminary experiments in brain slices and in vivo, we found that mouse models of 22q11DS have substantial deficits in synaptic transmission and short-term plasticity at TC pathways to the auditory cortex. In this proposal, we will use single-cell electrophysiology, 2-photon imaging, 2-photon glutamate uncaging, optogenetics, and molecular tools to identify the cellular and molecular mechanisms of TC deficiencies in mouse models of 22q11Ds. Using multiple available strains of mutant mice that carry deletions of clusters of genes or individual genes that map within the large 22q11 microdeletion, we will identify the gene(s) whose deletion underlies TC deficits in these mice. We will also perform in vivo 2-photon imaging to observe abnormal spontaneous activity in individual neurons of the auditory cortex. Abnormal neuronal activity in the auditory cortex has been reported in patients who experience auditory hallucinations, which are most predominant in SCZ. Ultimately, we expect to identify the culprit gene(s) and synaptic targets that cause TC abnormalities and abnormal cortical activity in these mouse models of SCZ. This information will provide a framework for the future development of specific therapeutic interventions to alleviate positive symptoms in patients with this catastrophic disease.