Experience-Dependent Reorganization of Excitatory Synapse Connectivity

兴奋性突触连接的经验依赖性重组

• 批准号: 10062341
• 负责人: Jen Qian Pan
• 金额: $ 70.46万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062341
• 关键词: Experience; Dependent; Reorganization; Excitatory; Synapse

Overwhelming genetic evidence in neuropsychiatric disorders points towards the excitatory synapse and plasticity components, essential for experience-dependent optimization of the neural circuit. This leads to the hypothesis that dysregulation in experience-dependent developmental plasticity caused by the molecular and cellular deficit leads to behavioral abnormalities. It is therefore essential to understand how experience sculpts the functional connection of excitatory synapses during development; and how under the pathological condition, this impaired mechanism derails the normal developmental trajectory. Using the mouse primary visual cortex (V1) as the model system, we have shown that during the functional maturation of excitatory synapses, AMPA receptor-mediated synaptic transmission remains at equilibrium during the critical period. The maintenance of this equilibrium requires neurogranin (Ng), a postsynaptic calmodulin (CaM)-binding protein important for synaptic plasticity, which is associated with schizophrenia and mental retardation. Two antagonizing mechanisms, experience-dependent AMPAR-silent synapse conversion and experience-dependent synapse elimination, hinge upon Ng for constructive synaptic refinement during the critical period. Our preliminary studies show that decreasing Ng levels led to delayed developmental switch of the NMDA receptor subunits, and shift in neuronal phosphorylation profiles. We hypothesize that Ng regulates experience-dependent organization of excitatory synaptic connectivity via controlling Ca/CaM- dependent phosphatase activities, which determine synaptic NMDAR composition and activity during development (critical components associated with schizophrenia). Using a combination of virus-mediated gene manipulation, electrophysiology, morphological analysis and behavioral interrogation, we will elucidate the molecular pathways governing experience-dependent refinement of excitatory synaptic connectivity during development, essential for sensory perception. Our study will help understand the molecular mechanisms important for calcium homeostasis in health and diseases, and may provide therapeutic substrate for pharmacological interventions for schizophrenia patients.

压倒性的神经精神疾病遗传证据指向兴奋性突触， 可塑性成分，对神经回路的经验依赖性优化至关重要。这导致 这一假说认为，经验依赖性发育可塑性的失调是由 分子和细胞缺陷导致行为异常。因此，必须了解如何 经验塑造了兴奋性突触在发育过程中的功能连接;以及在这种情况下， 在病理条件下，这种受损的机制偏离了正常的发育轨迹。使用 以小鼠初级视皮层（V1）为模型系统，我们已经证明，在功能成熟过程中， 兴奋性突触，AMPA受体介导的突触传递保持在平衡期间， 关键时期。这种平衡的维持需要神经颗粒蛋白（Ng），一种突触后钙调蛋白 （钙调素）结合蛋白对突触可塑性很重要，与精神分裂症和精神分裂症有关。 迟钝两种拮抗机制，经验依赖性AMPAR沉默突触转换和 经验依赖性突触消除，取决于Ng的建设性突触细化期间， 关键时期。我们的初步研究表明，降低Ng水平导致发育转换延迟 的NMDA受体亚基，并在神经元磷酸化的档案转变。我们假设Ng 通过控制Ca/CaM调节兴奋性突触连接的经验依赖性组织， 依赖性磷酸酶活性，其决定突触NMDAR的组成和活性， 发展（与精神分裂症相关的关键组成部分）。使用病毒介导的 基因操作，电生理学，形态分析和行为审讯，我们将阐明 控制兴奋性突触连接的经验依赖性细化的分子途径 在发育过程中，对感官知觉至关重要。我们的研究将有助于理解 在健康和疾病中钙稳态的重要机制，并可提供治疗 用于精神分裂症患者的药物干预的底物。