Input competition and synaptic modification during developmental remodeling

描述（由申请人提供）：本提案的总体目的是了解中枢神经系统（CNS）发育过程中如何实现精确的神经连接。轴突与其突触后目标之间的精确连接对于中枢神经系统的正常功能至关重要。这些联系是在早期发育过程中通过引导线索大致建立起来的，随后以活动依赖的方式进行微调。后一种微调过程涉及突触连接的稳定和消除。人们普遍认为，收敛输入之间的竞争在这一过程中起着重要作用，尽管这种竞争的细胞基础在中枢神经系统中知之甚少。此外，虽然人们普遍认为突触修饰可能是神经元重塑的基础，但突触的消除是否涉及长期抑制（LTD）样的可塑性形式尚不清楚。为了解决这两个关键问题，我们将使用一个经过充分研究的活动依赖微调模型：两个眼睛输入到外侧膝状核（LGN）的分离。最初，LGN神经元接受来自对侧和同侧眼睛的会聚功能突触输入。当对侧眼输入被保留时，同侧输入随后被撤回，它们的突触被消除。这种分离过程依赖于活动，需要两个眼睛输入之间的竞争。在本提案中，我们将回答两个重要问题：(1)收敛输入如何竞争？(2)突触抑制是否发生在同侧眼输入的突触消除和撤回之前？这些问题将使用一种独特的体外完整大鼠LGN制剂来解决，其中两个眼睛输入是完整的，可以独立电刺激。单个突触的位置和特性将使用记录和成像方法相结合的方法进行检查。从这项工作中获得的见解将为未来研究中枢神经系统突触消除和理解输入竞争、突触修饰和结构重塑的关系奠定基础。此外，获得的结果也可能揭示与神经发育障碍相关的各种疾病。从这一建议中获得的见解将为未来中枢神经系统突触消除的研究奠定基础，并为理解输入竞争、突触修饰和结构重塑的关系奠定基础。此外，获得的结果还将揭示与神经发育障碍相关的各种疾病。

Description (provided by applicant): The general purpose of this proposal is to understand how precise neural connections are achieved during the development of the central nervous system (CNS). Precise connections between axons and their postsynaptic targets are essential for the proper functions of the central nervous system. These connections are roughly established by guidance cues during early development and are subsequently fine-tuned in an activity-dependent manner. The latter fine-tuning process involves stabilization and elimination of synaptic connections. It is generally accepted that competition between converging inputs plays an important role in this process although the cellular basis of this competition is poorly understood in the CNS. In addition, while it is generally agreed that synaptic modifications may underlie neuronal remodeling, whether a long-term depression (LTD)-like form of plasticity is involved in the elimination of synapses is unclear. To address these two critical issues, we will use one well-studied model of activity-dependent fine-tuning: the segregation of two eyes inputs to the lateral geniculate nucleus (LGN). Initially LGN neurons receive converging functional synaptic inputs from both contralateral and ipsilateral eyes. While the contralateral eye inputs are retained, the ipsilateral inputs are subsequently withdrawn and their synapses are eliminated. This segregation process is activity-dependent and requires competition between two eye inputs. In this proposal, we will answer two important questions: (1) how does converging inputs compete? (2) Does synaptic depression occur prior to synapse elimination and withdrawal of ipsilateral eye inputs? These questions will be addressed using a unique in vitro intact rat LGN preparation in which two eye inputs are intact and can be electrically stimulated independently. The locations and properties of individual synapses will be examined using a combination of recording and imaging methods. Insights obtained from this work will form the foundation for future examination of synapse elimination in the CNS and to understand the relationship of input competition, synaptic modification and structural remodeling. In addition, the obtained results may also shed light on various diseases associated with the disorders of neural development. PUBLIC HEALTH RELEVANCE Insights obtained from this proposal will form the foundation for future examination of synapse elimination in the central nervous system and to understand the relationship of input competition, synaptic modification and structural remodeling. In addition, the obtained results will also shed light on various diseases associated with the disorders of neural development.