How do neurons in the brain decide to refine their synaptic connections in vivo?

大脑中的神经元如何决定在体内完善其突触连接？

• 批准号: 10608368
• 负责人: Chinfei Chen
• 金额: $ 86.96万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608368
• 关键词: Astrocytes; Axon; Biosensor; Brain; Cell Adhesion Molecules; Data; Defect; Development; Disease; Dorsal; Equilibrium; Etiology; Eye; Fibroblast Growth Factor Receptor 2; Functional disorder; Image; Impairment; In Vitro; JAK2 gene; Lateral Geniculate Body; Mental disorders; Molecular; Mus; Mutant Strains Mice; Neurons; PTPNS1 gene; Pathway interactions; Pattern; Physiological; Play; Process; Protein Tyrosine Kinase; Punishment; Regulation; Retina; Role; Schizophrenia; Signal Transduction; Site; Structure; Synapses; System; Testing; Visual; Visual System; Visualization; Work; autism spectrum disorder; design; experience; experimental study; in vivo; insight; nervous system disorder; neural; neural circuit; neural network; neuropsychiatric disorder; novel; novel therapeutic intervention; postnatal; postsynaptic neurons; prevent; response; retinogeniculate; segregation; superior colliculus Corpora quadrigemina; synaptogenesis; tool; two-photon

Project Summary The formation of functional neural circuits is critical for the proper functioning of the brain. To establish the most efficient synaptic circuits, synaptic connections must be refined by neural activity during development. However, the manner and molecules by which synapse refinement is regulated remain to be elucidated. We have established mouse in vivo systems, in which neural activity can be conditionally controlled, and showed that inactive synaptic connections are eliminated during development, but they are eliminated only when there are other active connections with which to compete. This suggests that active connections send a "punishment" signal to inactive ones and instruct them to leave by triggering "elimination" signals within the inactive synapses. Active connections are kept by the presence of "stabilization" signals. By performing various screens, we have identified that the tyrosine kinases Pyk2 and JAK2 serve as "elimination" signals of inactive synaptic connections during development. Pyk2 and JAK2 are turned on at inactive synapses in response to "punishment" signals sent from active synapses to drive inactive synapse elimination. Furthermore, we found that a cell adhesion molecule SIRPa from postsynaptic neurons serves as a "stabilization" signal for active synapses. Together, we propose that neurons calculate the balance between the "elimination" signals (Pyk2/JAK2) and the "stabilization" signals (SIRPa) and determine whether to eliminate or stabilize their synaptic connections. Interestingly, our recent preliminary data suggest that the elimination signals Pyk2 and JAK2 have different roles, with Pyk2 in synapse elimination and JAK2 in axon elimination. Additionally, we found that astrocytic ensheathing of synapses also plays important roles in synapse elimination. To further uncover the molecular mechanisms underlying synapse refinement in vivo, we propose to: Aim 1. Investigate the differential roles of Pyk2 and JAK2 for synapse and axon refinement and how SIRPa regulates their activity. Aim 2: Visualize the elimination signals and their regulation of activity-dependent synapse/axon refinement in vivo. Aim 3: Examine the role(s) of astrocytic sheaths in regulating the elimination signals and synapse refinement. Our project will molecularly delineate how neurons decide to establish functional synaptic connections in the mammalian brain. Many forms of mental illness including autism and schizophrenia are associated with abnormal alterations in synapse refinement. Thus, our studies should also yield novel insights into the etiology and treatment of such disorders.

项目摘要 功能神经回路的形成对于大脑的正确功能至关重要。建立 最有效的突触电路，突触连接必须通过发育过程中的神经活动来完善。 但是，调节突触细化的方式和分子仍尚待阐明。 我们已经建立了体内系统的小鼠，可以有条件地控制神经活动，并且 表明在开发过程中消除了无效的突触连接，但仅消除它们 当还有其他积极的连接可以竞争时。这表明主动连接发送 “惩罚”信号不活动，并指示他们通过触发“消除”信号离开的信号 非活动突触。主动连接通过“稳定”信号的存在保持。通过执行各种 屏幕，我们已经确定酪氨酸激酶pyk2和jak2是无效的“消除”信号 开发过程中的突触连接。 pyk2和jak2在不活动的突触时被打开 从主动突触发送的“惩罚”信号以驱动无症突触消除。此外，我们发现 来自突触后神经元的细胞粘附分子siRPA充当活性的“稳定”信号 突触。我们共同提出，神经元计算“消除”信号之间的平衡 （PYK2/JAK2）和“稳定”信号（SIRPA），并确定是消除还是稳定其 突触连接。有趣的是，我们最近的初步数据表明，消除信号是Pyk2和 JAK2具有不同的作用，PYK2在消除突触中，而JAK2在消除轴突中。另外，我们 发现突触的星形胶质细胞在突触消除中也起着重要作用。 为了进一步发现体内突触细化的分子机制，我们建议： AIM 1。研究Pyk2和Jak2的差异作用以进行突触和轴突细化以及SIRPA如何 调节他们的活动。目标2：可视化消除信号及其对活动依赖性的调节 体内突触/轴突细化。目标3：检查星形胶质鞘在调节消除中的作用 信号和突触细化。 我们的项目将分子描述神经元如何决定在 哺乳动物的大脑。包括自闭症和精神分裂症在内的许多形式的精神疾病与 突触细化的异常改变。因此，我们的研究还应对病因产生新的见解 和治疗此类疾病。