Identification of synaptic mechanisms of 22q11 deletion syndrome

描述(申请人提供)：22q11缺失综合征(22q11DS)，又称瓣膜综合征或DiGeorge综合征，是人类最常见的微缺失综合征。几乎所有患有22q11DS的患者都会出现认知障碍，大约30%的患者会在青春期或成年早期发展为精神分裂症或分裂情感障碍。已经在22q11DS患者和这种疾病的小鼠模型DF(16)1/+小鼠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(S)仍然不清楚。最近，我们发现突触传递的长时程增强(LTP)发生了实质性的改变，LTP是突触可塑性的一种主要形式，也是某些形式学习和记忆的细胞底物 在DF(16)1/+小鼠中。我们确定这些变化是由兴奋性突触的突触前功能异常引起的。进一步的实验表明，突触前功能的增加是由于大的微缺失中的两个基因组区域的缺失引起的，即DF(16)2和DF(16)5。对DF(16)2区域单个基因缺失的小鼠进行筛选发现，MicroRNA处理基因Dgcr8的缺失上调了兴奋性神经元中的SERCA2，并导致神经递质异常释放和LTP。DF(16)5区域内的罪魁祸首基因的身份尚不清楚。在这一应用中，我们建议使用电生理和分子工具、双光子激光扫描显微镜和双光子去势来鉴定负责SERCA2上调和突触可塑性缺陷的microRNA(S)。利用我们实验室最近培育的基因敲除小鼠，我们还将识别出DF(16)5区域内的元凶基因(S)。最后，我们建议测试内质网在22q11DS小鼠模型突触前表型中的作用。这些信息将为预防或缓解22q11DS患者认知障碍的治疗干预措施的未来发展提供一个框架。 与公共卫生相关：22q11染色体杂合缺失大大增加了个体患精神分裂症的风险。携带这些缺失的患者和小鼠模型的认知功能明显受损。为了更好地了解这些缺陷并找到原因基因和下游信号通路，我们将研究建立22q11缺失综合征模型的突变小鼠突触异常的机制。

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. PUBLIC HEALTH RELEVANCE: Heterozygous deletions within the 22q11 chromosome substantially increase an individual's risk for schizophrenia. Cognitive function is characteristically impaired in patients and mouse models that carry these deletions. To better understand these deficits and find the causal genes and downstream signaling pathways, we will investigate the mechanisms of synaptic abnormalities in mutant mice that model 22q11 deletion syndrome.