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

项目摘要 功能神经回路的形成对大脑的正常运作至关重要。要建立 作为最有效的突触回路，突触连接必须在发育过程中通过神经活动来完善。 然而，调控突触细化的方式和分子仍有待阐明。 我们已经建立了小鼠体内系统，在其中神经活动可以有条件地控制，并且 显示不活跃的突触连接在发育过程中被消除，但它们只被消除 当有其他活跃的连接可与之竞争时。这表明活动连接会发送一个 “惩罚”信号给不活跃的人，并通过触发 不活跃的突触。活跃的连接通过“稳定”信号的存在来保持。通过执行各种 屏幕上，我们已经确认酪氨酸激酶PYK2和JAK2作为不活跃的“消除”信号 发育过程中的突触连接。Pyk2和JAK2在不活跃的突触上被激活，以响应 “惩罚”信号从活跃的突触发出，以驱动不活跃的突触消除。此外，我们发现， 来自突触后神经元的细胞黏附分子SIRPA是激活的稳定信号 突触。总而言之，我们认为神经元计算“消除”信号之间的平衡 (PYK2/JAK2)和“稳定”信号(SIRPA)，并确定是否消除或稳定其 突触连接。有趣的是，我们最近的初步数据表明，消除信号PYK2和 JAK2在突触消除和轴突消除中起着不同的作用。此外，我们 研究发现，突触的星形细胞包膜在突触消除过程中也起着重要作用。 为了进一步揭示体内突触细化的分子机制，我们建议： 目的1.研究PYK2和JAK2在突触和轴突细化中的不同作用以及SIRPA是如何 来规范他们的活动。目标2：可视化依赖活动的消除信号及其调节 体内突触/轴突的细化。目的3：研究星形胶质细胞鞘在调节排泄中的作用(S) 信号和突触的精细化。 我们的项目将从分子上描绘神经元如何决定建立功能性突触连接。 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都与 突触精化的异常改变。因此，我们的研究也应该对病因学产生新的见解。 以及这类疾病的治疗。

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.