Identification of synaptic mechanisms of 22q11 deletion syndrome

描述（由申请人提供）：22 q11缺失综合征（22 q11 DS），也称为腭心面综合征或DiGeorge综合征，是人类最常见的微缺失综合征。几乎所有22 q11 DS患者都会出现认知缺陷，大约30%的患者在青春期或成年早期会出现精神分裂症或情感障碍。在22 q11 DS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。近年来，我们发现突触传递的长时程增强（long-term potentiation，LTP）是突触可塑性的主要形式，也是某些学习记忆活动的细胞基础 Df（16）1/+小鼠。我们确定这些变化是由兴奋性突触的异常突触前功能引起的。进一步的实验表明，突触前功能的增加是由大微缺失中的2个基因组区域Df（16）2和Df（16）5的缺失引起的。对Df（16）2区域内个别基因缺失的小鼠进行筛选，发现microRNA加工基因Dgcr 8的缺失上调兴奋性神经元中的肌浆网ATP酶2（SERCA 2），并导致异常的神经递质释放和LTP。Df（16）5区域内的罪魁祸首基因的身份仍然未知。在本申请中，我们建议通过使用电生理学和分子工具、双光子激光扫描显微镜和双光子解开来鉴定负责SERCA 2上调和突触可塑性缺陷的microRNA。使用我们实验室最近开发的敲除小鼠，我们还将鉴定Df（16）5区域内的罪魁祸首基因。最后，我们建议测试的作用，内质网在突触前表型的小鼠模型的22 q11 DS。这些信息将为未来开发预防或缓解22 q11 DS患者认知缺陷的治疗干预提供框架。

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.