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

基本信息

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
项目类别：
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&apos 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

项目摘要

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）是一种毁灭性疾病，影响了世界人口的大约1％，其特征是一系列症状，包括幻觉和妄想（积极症状），反社会行为，反社会行为和钝性情绪（负面症状），在工作记忆，执行功能和记忆和记忆和记忆（Cognity and Consive）中的缺陷（负面症状（负面症状））。这些症状的基础机制尚不清楚，这主要是由于缺乏对该疾病进行建模的有效实验方法。 22q11.2-Deletion综合征（22Q11DS），也称为Velocardiofacialsyndrome或Digeorge综合征，是人类中最常见的微缺失综合征。 SCZ在青春期或成年早期患有22q11ds的患者中大约有30％。通过复制工作记忆，学习和记忆以及其他症状中的缺陷来构建和验证22q11ds的鼠标模型。使用这些突变小鼠，我们和其他人确定了22q11ds认知症状的基础的细胞和分子机制。但是，在小鼠中不能说服幻觉等自我报告的症状。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，这些预测是由于丘脑皮层（TC）途径的缺陷导致的，这些幻觉将投射到感官皮层的途径。在我们在大脑切片和体内的初步实验中，我们发现22q11ds的小鼠模型在TC通往听觉皮层的TC途径的突触传播和短期可塑性方面存在大量缺陷。在此提案中，我们将使用单细胞电生理学，2光片成像，2光谷氨酸渗透，光遗传学和分子工具来鉴定22q11ds小鼠模型中TC缺乏的细胞和分子机制。使用多种可用的突变小鼠菌株，这些突变小鼠的基因或单个基因簇的缺失在大型22q11微骨骼中的地图，我们将确定其缺失是这些小鼠中TC缺陷的基因。我们还将执行体内2光子成像，以观察听觉皮层单个神经元的异常自发活性。据报道，经历听觉幻觉的患者，在听觉皮层中的神经元活性异常，这在SCZ中最为主导。最终，我们希望在这些小鼠SCZ模型中鉴定导致TC异常和皮质活性异常的罪魁祸首和突触靶标。该信息将为未来开发特定的治疗干预措施的发展提供一个框架，以减轻这种灾难性疾病患者的积极症状。