Identification of synaptic mechanisms of 22q11 deletion syndrome

22q11 缺失综合征突触机制的鉴定

• 批准号: 8711559
• 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: 2012
• 资助国家: 美国
• 起止时间: 2012-08-08 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711559
• 关键词: 22q11; 22q11 Deletion Syndrome; ATP phosphohydrolase; Adolescence; Age; Behavioral; Bioinformatics; Brain; Calcium; Cardiovascular Abnormalities; Chromosomes; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 22; Cognitive; Cognitive deficits; Complex; Craniofacial Abnormalities; Defect; Development; DiGeorge Syndrome; Disease; Endoplasmic Reticulum; Evaluation; Event; Excitatory Synapse; Exhibits; Frequencies; Future; Gene Deletion; Genes; Genetic; Genetic Risk; Genomics; Glutamates; Government; Homologous Gene; Human; Human Chromosomes; Hypocalcemia result; Image; Immunologic Deficiency Syndromes; Impairment; Individual; Knockout Mice; Laboratories; Laser Scanning Microscopy; Learning; Learning Disabilities; Live Birth; Long-Term Potentiation; Mediating; Memory; Mental disorders; MicroRNAs; Molecular; Monozygotic Twinning; Monozygotic twins; Mus; Neurobehavioral Manifestations; Pathogenesis; Patients; Persons; Phenotype; Presynaptic Terminals; Processed Genes; Proteins; Reticulum; Risk; Role; Saint Jude Children' s Research Hospital; Schizoaffective Disorders; Schizophrenia; Signal Pathway; Synapses; Synaptic Transmission; Synaptic plasticity; Syndrome; Testing; Therapeutic Intervention; Transcript; Up-Regulation; Viral; cognitive function; emerging adult; excitatory neuron; expression vector; inhibitor/antagonist; microdeletion; mouse model; mutant; mutant mouse model; neurotransmitter release; presynaptic; prevent; research study; screening; synaptic function; tool; two-photon

DESCRIPTION (provided by applicant): The 22q11 deletion syndrome (22q11DS), also known as velocardiofacialsyndrome or DiGeorge syndrome, is the most common microdeletion syndrome in humans. Cognitive deficits occur in virtually all patients with 22q11DS, and schizophrenia or schizoaffective disorder develops in approximately 30% during their adolescence or early adulthood. Deficits in learning and memory have been identified in patients with 22q11DS and in Df(16)1/+ mice, the mouse model of this disease. However, the cellular mechanisms and gene(s) responsible for these deficits remain unknown. Recently, we discovered that long-term potentiation (LTP) of synaptic transmission, a major form of synaptic plasticity and cellular substrate of certain forms of learning and memory, is substantially altered in Df(16)1/+ mice. We determined that these changes are caused by the abnormal presynaptic function at excitatory synapses. Further experiments revealed that the increase in presynaptic function was caused by the deletion of 2 genomic regions within the large microdeletion, Df(16)2 and Df(16)5. Screening of mice with deletions of individual genes within the Df(16)2 region revealed that a deletion of the microRNA-processing gene Dgcr8 upregulates sarco(endo)plasmic reticulum ATP-ase 2 (SERCA2) in excitatory neurons and leads to abnormal neurotransmitter release and LTP. The identity of the culprit gene within the Df(16)5 region remains unknown. In this application, we propose to identify the microRNA(s) responsible for the upregulation of SERCA2 and the defects in synaptic plasticity by using electrophysiological and molecular tools, two-photon laser scanning microscopy, and two-photon uncaging. Using knockout mice recently developed in our laboratory, we will also identify the culprit gene(s) within the Df(16)5 region. Finally, we propose to test the role of the endoplasmic reticulum in presynaptic phenotypes of mouse models of 22q11DS. This information will provide a framework for the future development of therapeutic interventions to prevent or alleviate cognitive deficits in patients with 22q11DS.

描述（由申请人提供）：22q11缺失综合征（22q11DS），也称为速心面综合征或DiGeorge综合征，是人类最常见的微缺失综合征。几乎所有22q11DS患者都有认知缺陷，大约30%的患者在青春期或成年早期出现精神分裂症或分裂情感性障碍。在22q11DS患者和Df(16)1/+小鼠（该疾病的小鼠模型）中发现了学习和记忆缺陷。然而，导致这些缺陷的细胞机制和基因仍然未知。最近，我们发现突触传递的长期增强（LTP）是突触可塑性的主要形式，也是某些形式的学习和记忆的细胞基础，它发生了实质性的改变