During mammalian development, neurons in the visual cortex differentiate from immature cells with few processes into elaborate, richly interconnected components of a network capable of complex information processing. The exquisite precision of these thousands of connections within visual cortex is established during a critical period of development, when immature neural connections are remodeled by visual experience to generate adult patterns of connectivity. Although this activity-dependent competition has been the focus of much research at the system level, there is very little known about the cellular and molecular changes that occur at individual synapses during initial synapse formation, and then subsequently during the synaptic strengthening and weakening that underlie synaptic refinement. The central goal of this proposal is to investigate the cellular and molecular mechanisms of synapse formation and refinement in the developing visual cortex. Specifically, the molecular and physiological changes that occur as cortical synapses form and are strengthened and stabilized, or are weakened and eliminated, will be studied in real-time using simultaneous time-lapse confocal imaging of fluorescently-tagged synaptic proteins and whole-cell path-clamp recording of the activity of individual, identified synapses.
These specific aims of this proposal are: (1) to define the sequence of cellular and molecular events that occurs during synaptogenesis between glutamatergic neurons from the visual cortex, (2) to identify the cellular and molecular events that mediate activity-dependent refinement at excitatory synapses between visual cortical neurons, and (3) to test the hypothesis that the hypothesis that the neurotrophins regulate the formation and/or refinement of glutamatergic synapses between visual cortical neurons. The results of 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 and refinement could revolutionize our ability to identify, prevent, and treat these developmental disorders.
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