Input competition and synaptic modification during developmental remodeling

描述(由申请人提供)：本建议的总体目的是了解在中枢神经系统(CNS)的发育过程中如何实现精确的神经连接。轴突和它们的突触后目标之间的精确联系对于中枢神经系统的正常功能是必不可少的。这些联系大致是在早期发育期间由指导线索建立的，随后以依赖活动的方式进行微调。后一种微调过程包括稳定和消除突触连接。人们普遍认为，汇聚的输入之间的竞争在这一过程中发挥了重要作用，尽管这种竞争的细胞基础在中枢神经系统中鲜为人知。此外，虽然人们普遍认为突触的修改可能是神经元重塑的基础，但是否长期抑制(LTD)样的可塑性形式参与突触的消除尚不清楚。为了解决这两个关键问题，我们将使用一个研究得很好的活动依赖微调模型：双眼输入到外侧膝状体核(LGN)的分离。最初，LGN神经元从对侧和同侧眼接受会聚的功能性突触输入。当对侧眼的输入被保留时，同侧的输入随后被撤回，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。在这个提案中，我们将回答两个重要的问题：(1)汇聚的输入是如何竞争的？(2)突触抑制是否发生在突触消除和同侧眼输入退出之前？这些问题将通过一种独特的体外完整的大鼠LGN准备来解决，在这种准备中，两个眼睛输入是完整的，可以独立地进行电刺激。将结合记录和成像方法来检查单个突触的位置和属性。这项工作获得的见解将为未来研究中枢神经系统突触消除以及理解输入竞争、突触修饰和结构重塑的关系奠定基础。此外，所获得的结果还可能有助于揭示与神经发育障碍相关的各种疾病。从这项提案中获得的与公共健康相关的见解将为未来检查中枢神经系统中突触的消除以及理解输入竞争、突触修饰和结构重塑之间的关系奠定基础。此外，所获得的结果还将有助于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 While the contralateral eye inputs are retained, the ipsilateral inputs are subsequently withdrawn and their synapses are eliminated.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.