The mammalian visual system requires the proper formation of exquisitely precise circuits to function correctly. These neuronal circuits are assembled during development by the formation of synaptic connections between thousands of differentiating neurons. Although the formation of glutamatergic synapses is critical for the proper function of the visual system, little is known about how these synapses are formed. Recent work has begun to identify some of the early cellular events in synapse formation as well as the molecular signals that initiate this process. Despite the wealth of information published on this topic in the past few years, some of the most fundamental questions about synapse formation remain unanswered. In particular, the basic mechanisms of transport of synaptic proteins in axons and dendrites before synapse formation have just begun to be identified. How these mechanisms are altered and regulated during the accumulation of synaptic protein at new mammalian synapses remains a mystery. Defining these basic mechanisms of transport and their regulation is critical to understand how synaptogenic signals might alter and direct transport of synaptic proteins to new synapses. The central goal of this proposal is to investigate the molecular mechanisms of the transport and recruitment of synaptic proteins to new synapses between visual cortical neurons. We propose to address these issues directly by combining techniques that allow us to visualize and focally manipulate the transport and recruitment of fluorescently-tagged proteins during synapse formation between dissociated, cultured visual cortical neurons.
The specific aims of this proposal are: (1) to identify intracellular signaling pathways that regulate the transport of synaptic vesicle precursors, (2) to identify intracellular signaling pathways that regulate the transport of NMDA receptors, and (3) to determine how transport of synaptic proteins is altered in response to synaptogenic signals. Results from these experiments will be essential for a comprehensive understanding of the cellular and molecular mechanisms underlying the development of the visual cortex. These results will also provide insight into the mechanisms responsible for amblyopia, as well as possible approaches to therapy. More generally, defects in synapse formation are likely to cause many neurodevelopmental disorders from mental retardation, to autism, to schizophrenia. Understanding the cellular and molecular mechanisms of synapse formation could revolutionize our ability to identify, prevent, and treat these developmental disorders. ? ?
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