Towards understanding cellular mechanisms of positive symptoms of schizophrenia

理解精神分裂症阳性症状的细胞机制

• 批准号: 8875764
• 负责人: Stanislav S Zakharenko
• 金额: $ 43.75万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875764
• 关键词: 22q11; 22q11 Deletion Syndrome; 22q11.2; Adolescence; Affect; Animals; Antipsychotic Agents; Area; Attention; Auditory; Auditory Hallucination; Auditory area; Biological; Biological Markers; Brain; Brain region; Ca(2+)-Transporting ATPase; Calcium; Cells; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 22; Cognition; Data; Defect; Delusions; Development; DiGeorge Syndrome; Diagnosis; Disease; Disease model; Electrophysiology (science); Emotions; Endoplasmic Reticulum; Evaluation; Event; Functional Imaging; Future; Gene Cluster; Generations; Genes; Genetic; Genomic Segment; Glutamates; Government; Hallucinations; Health; Hippocampus (Brain); Homologous Gene; Human; Human Chromosomes; Image; Individual; Knock-out; Laboratory mice; Learning; Measures; Memory; Modeling; Molecular; Mus; Mutant Strains Mice; Neurobehavioral Manifestations; Neurons; Neurosciences; Pathway interactions; Patient Self-Report; Patients; Pattern; Persons; Phenotype; Play; Population; Poverty; Pre-Clinical Model; Reporting; Research; Risk; Role; Saint Jude Children' s Research Hospital; Schizophrenia; Short-Term Memory; Slice; Speech; Study models; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Syndrome; Testing; Thalamic structure; Therapeutic Intervention; Up-Regulation; Work; age related; antisocial behavior; base; calcium indicator; emerging adult; executive function; experience; genetic predictors; human data; in vivo; information processing; microdeletion; mouse model; mutant mouse model; optogenetics; postsynaptic; presynaptic; research study; sensory cortex; theories; tool; two-photon

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.

描述（由申请人提供）：精神分裂症 (SCZ) 是一种毁灭性的疾病，影响着世界上大约 1% 的人口，其特征是一系列症状，包括幻觉和妄想（阳性症状）、反社会行为和迟钝情绪（阴性症状） ）、工作记忆、执行功能以及学习和记忆缺陷（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)，也称为心面综合征或 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会出现 SCZ。通过复制工作记忆、学习和记忆以及其他症状的缺陷，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 认知症状背后的细胞和分子机制。然而，自我报告的症状（例如幻觉）无法在小鼠身上建立令人信服的模型。在此应用中，我们建议测试一些最近的神经科学理论和人类成像数据的预测，即幻觉是由投射到感觉皮层的丘脑皮质（TC）通路缺陷引起的。在我们对脑切片和体内的初步实验中，我们发现 22q11DS 的小鼠模型在突触传递和通往听觉皮层的 TC 通路的短期可塑性方面存在严重缺陷。在本提案中，我们将使用单细胞电生理学、2-光子成像、2-光子谷氨酸解笼锁、光遗传学和分子工具来识别 22q11D 小鼠模型中 TC 缺陷的细胞和分子机制。使用多种可用的突变小鼠品系，这些小鼠携带基因簇或单个基因的缺失， 通过绘制大 22q11 微缺失内的图谱，我们将鉴定其缺失导致这些小鼠 TC 缺陷的基因。我们还将进行体内 2 光子成像，以观察听觉皮层单个神经元的异常自发活动。据报道，出现幻听的患者听觉皮层神经元活动异常，这在 SCZ 中最为常见。最终，我们希望找出导致这些 SCZ 小鼠模型中 TC 异常和异常皮质活动的罪魁祸首基因和突触靶标。这些信息将为未来开发特定治疗干预措施提供框架，以减轻这种灾难性疾病患者的阳性症状。