NMDARs play essential roles in the development and refinement of neuronal connections by contributing to the maturation and stabilization of synapses and dendritic spines. A key step regulating synaptic stabilization is the transition from developmental to mature NMDAR subtypes during a critical postnatal period of brain development. However, little is known about the molecular mechanisms for removing or replacing NMDARs at the synapse.This proposal will investigate molecular/cell biological mechanisms that mediate the synaptic exchange of NMDARs, and the role they play in establishing appropriate synaptic connectivity. Our previous studies indicate that a principal regulator of NMDARs at immature synapses is the inhibitory NR3A subunit. Specifically, NR3A d irects for synaptic removal of NMDARs via rapid internalization. NR3A-mediated internalization is tightly regulated as it requires both activity and the recruitment of a neuronal-specific adaptor, PACSIN1/syndapin1. Our working hypothesis is that rapid dow nregulation of NMDARs-containing NR3A from synapses provide a critical signal that allows enhanced localization of mature NMDARs at synapses and thus stabilizes neuronal circuits during development. The experiments in this proposal are designed to test thi s model directly by analyzing how changes in NR3A expression affect the development of correct numbers of synapses and dendritic spines. The proposal represents a three-tiered approach to understand the role of specific pathways of NMDAR endocytic traffic king, starting with the basic characterization of a novel cell biological mechanism in vitro, the manipulation of molecular elements of this pathway to study its importance for the proper development of synaptic connections, and using a complementary genet ic approach to determine the extent to which inclusion of NR3A in the NMDAR complex controls spine morphogenesis and its possible causative role in neurodevelopmental disorders such as schizophenia.
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