Identification of synaptic mechanisms of 22q11 deletion syndrome

22q11 缺失综合征突触机制的鉴定

基本信息

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
项目类别：
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&apos 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

项目摘要

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.