Input competition and synaptic modification during developmental remodeling

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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 While the contralateral eye inputs are retained, the ipsilateral inputs are subsequently withdrawn and their synapses are eliminated.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.