A striking feature of the developing central nervous system is the absolute precision with which synaptic circuitry first forms. At the same time, many synapses are eliminated, or rearranged and final synapse location and number is influenced by activity and trophic factors. A broadly accepted model is that genetically programmed factors, such as the """"""""cytochemical affinities"""""""" envisioned by Sperry, bring axons and target neurons into close proximity, and a low threshold recognition between pre- and postsynaptic partners is sufficient to trigger synapse assembly. Every synapse then exists in one of three states: labile, stable or regressed. The pre- and postsynaptic exchange of activity-dependent and/or independent signals, which could include greater or lesser degrees of molecular matching, promotes a shift in state, selectively stabilizing or destabilizing an interaction. Progressive rounds of stabilization and destabilization culminate in the final distribution of synapses. Consistent with this model, recognition between key cell adhesion molecule (CAM) partners, such as neurexins and neuroligins or SynCAMs can trigger assembly, and once formed, young, still-labile synapses are structurally and functionally distinct from mature synapses. Data from our lab and others indicate that young synaptic junctions require cadherin-based adhesion linked to the actin cytoskeleton, and that this contributes critically to normal synapse morphology and function. Cadherins do not act alone as they need at least the trigger actions of other CAMs, but whether and how cadherins interact with other synaptic CAMs has never been examined. Additionally, cadherins and actin do not play the same role at mature synapses, and while studies of individual CAMs have outlined important roles for SynCAMs, neuroligins, cadherins and integrins, synaptic structure has proven remarkably resilient to single molecule and even family deletion, and at this time virtually nothing is known about how CAM families work together to generate the trans-synaptic adhesive network at any age or synapse type. Thus, it is the goal of the first aim to determine the relationship between adhesive composition and synapse structure, identity, and maturational state. Several factors have been identified that can promote synapse stabilization, but equally important are the factors that can destabilize synapses and eliminate young, actin-linked junctions. In the second aim we will pursue our novel finding that protein synthesis regulates synapse activity and adhesive stability at young synapses. A growing body of work indicates that synapse maturation, stabilization, and the regulation of synapse adhesion contributes to a variety of devastating developmental disorders including autism and Down's syndrome. It is our hope that the results from this work can be used to identify and potentially to regulate key critical states of synapse development.

Public Health Relevance

The implications of this work are important for understanding a variety of neurological disorders that are thought to arise from defects in neural connectivity. Several studies support that schizophrenia, autism spectrum disorders and certain forms of mental retardation have at their root a defect in neural connectivity.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Morris, Jill A
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Icahn School of Medicine at Mount Sinai
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New York
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