Temporal requirements for N-cadherin in maintaining stability of synapses

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SPACE PROVIDED. It is well documented that the cell adhesion molecule N-cadherin is required for early brain development and establishment of synaptic connectivity. However, its role in maintaining synaptic form and function beyond initial synapse development and in maturity remains an open question. This is unclear in mammalian brain because genetic manipulations that have been used previously to modify N-cadherin function lead to extensive perturbations of brain organization, are embryonic lethal, or are not specific to N-cadherin. The overall goal of this proposal is to understand the contrilsutions of N-cadherin to synapse molecular composition and stability in the post-early developmental brain using mice harboring a conditional deletion of N-cadherin which commences in the third postnatal week. Molecular techniques will be used in conjunction with immunocytochemistry and microscopy to determine the extent to which N-cadherin affects synapse stability and organization. This proposal will also look at how N-cadherin's different functional domains contribute to synapse maintenance by utilizing mutant N-cadherin constructs that have a modified or are missing a particular domain. Using this strategy, the confounding antecedent roles of N-cadherin in development of basic brain structure, migration, axon growth and synaptogenesis can be bypassed to investigate the hypothesis that N-cadherin, selectively, is important for maintenance of synapse composition and stability. Relevance: Disruptions in synapse connectivity may be central to psychiatric diseases which manifest themselves after the period of early development, and include such disorders as schizophrenia, autism spectrum disorders, and Rett syndrome. Determining the fundamental role that synaptic proteins such as cadherins play in maintaining synapse architecture and connections can help us better understand how its dysfunction leads to psychiatric disorders. PHS416-1 (Rev.9/08) Page 2 Number pages consecutively at the tiottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. Kirschstein-NRSA Individual Fellowship Application NAME OF APPLICANT (Last, first, middle initial) Nikitczuk, Jessica S (To be completed by applicant- follow PHS 416-1 instructions) 18.