Molecular Analysis of Neural Circuit Excitation and Inhibition

电路连接性的发育性重塑是形成成熟的 组织大脑中的神经回路，优化它们的连接性，以便执行特定的 功能。重塑是由环境刺激和内在遗传共同触发的 机制和重塑过程中的缺陷被认为是导致 在各种神经发育和神经精神疾病中观察到的连接模式的改变 精神错乱。尽管这些发育过程对正常的大脑显然很重要 生理学和健康，我们对细胞和分子的理解存在重大差距 调节神经回路重塑的机制。 对遗传模型的研究已被证明在识别基本基因方面卓有成效。 神经回路发育和功能的潜在机制。我们之前的研究已经 开创了阐明突触规范机制的新方法 在基因上易驯化的模型线虫秀丽线虫中的连通性。在.期间 在之前的资金阶段，我们演示了突触后特化的重塑定位 对线虫运动回路中GABA能神经元的研究表明，新的 突触在重塑过程中与以前未定性的突触的生长有关 GABA能树突上的刺。此外，我们还发现了脊椎所需的一种新机制 突触生长和突触组装依赖于突触组织者神经毒素。这些 研究结果证明了该系统在识别具有保守作用的关键基因方面的优势。 塑造神经回路连接，使我们处于深入研究In的有利地位 活体分子机制。事实上，在支持这一申请的初步研究中，我们有 鉴定了哺乳动物染色质的同源结构域转录因子DVE-1 组织者SATB1/2作为调控突触重塑过程中突触消除的关键枢纽 马达电路。在本提案的目标1中，我们研究了一种新的转录网络控制 突触的拆解和消除。在目标2中，我们探索细胞和分子机制。 在电路重塑过程中新突触组装的基础上，重点关注 保守的突触组织者神经瑞新。 我们预计，我们对蠕虫中这种实验上易驯化的回路的研究将会有一个主要的 影响我们对参与电路重塑的分子过程的理解。 此外，我们预计我们确定的新分子和信号机制将是 治疗神经发育障碍的极佳候选者，包括 电路连接中断。

Developmental remodeling of circuit connectivity is a key process in shaping the mature organization of neural circuits in the brain, optimizing their connectivity in order to perform specific functions. Remodeling is triggered by both environmental stimuli and intrinsic genetic mechanisms, and deficits in remodeling processes are thought to be a primary factor underlying altered patterns of connectivity observed in a variety of neurodevelopmental and neuropsychiatric disorders. Despite the clear importance of these developmental processes for normal brain physiology and health, there are major gaps in our understanding of the cellular and molecular mechanisms that regulate neural circuit remodeling. Studies of genetic models have proven to be extremely fruitful for identifying fundamental mechanisms underlying neural circuit development and function. Our previous studies have pioneered new approaches for elucidating mechanisms for the specification of synaptic connectivity in a genetically tractable model, the nematode Caenorhabditis elegans. During the previous funding period, we demonstrated the remodeling of postsynaptic specializations located on GABAergic neurons in the C. elegans motor circuit, and showed that the formation of new synapses during remodeling is associated with the outgrowth of previously uncharacterized spines on GABAergic dendrites. Moreover, we uncovered a novel mechanism required for spine outgrowth and synapse assembly that depends on the synaptic organizer neurexin. These findings demonstrate the strength of this system for identifying key genes with conserved roles in shaping neural circuit connectivity and place us in a strong position for a deep investigation of in vivo molecular mechanisms. Indeed, in preliminary studies supporting this application we have identified the homeodomain transcription factor DVE-1, a homolog of mammalian chromatin organizers SATB1/2, as a key hub for regulation of synapse elimination during remodeling of the motor circuit. In Aim 1 of this proposal we investigate a novel transcriptional network controlling synapse disassembly and elimination. In Aim 2, we explore cellular and molecular mechanisms underlying the assembly of new synapses during circuit remodeling, focusing on the role of the conserved synaptic organizer neurexin. We expect that our studies of this experimentally tractable circuit in the worm will have a major impact on our understanding of the molecular processes involved in circuit remodeling. Additionally, we anticipate that the novel molecules and signaling mechanism we identify will be excellent candidates for therapeutic intervention to treat neurodevelopmental disorders involving disruptions in circuit connectivity.