The major aim of this research is to learn how neural activity ultimately leads to synapse remodeling and circuit change in the developing mammalian visual system. A central question under study is, what happens in the brain during early critical periods of development? Answers are key to understanding causes of developmental neurological disorders such as Dyslexia and Autism. The hypothesis examined is that molecules and mechanisms not only enable, but also negatively regulate, synaptic plasticity in developing and adult visual system. Four interrelated Specific Aims focus on specific candidate molecules on both sides of the equation: 1) Determine if ocular dominance (OD) plasticity in mouse visual cortex requires MARK signaling during and after the critical period. A microarray screen identified a """"""""common gene set"""""""" regulated by vision that are downstream targets of MARK. Experiments will block MARK function and examine consequences for OD plasticity. 2) Determine if SRF (Serum Response Factor) is required for OD plasticity. A conditional SRF knockout mouse will be used to examine whether SRF, a target of MARK, contributes to OD plasticity beyond, as well as during, the critical period. 3) Determine if PIRB, a novel immune receptor, limits the extent and/or duration of OD plasticity. We recently discovered that PIRB is expressed in CMS neurons. Preliminary studies in mutant mice lacking functional PIRB suggest that OD plasticity in visual cortex is enhanced. Experiments will characterize in detail visual system phenotypes of these mice in vivo. 4) Examine cellular mechanisms of synaptic plasticity in PIRB mutant mice. To establish mechanistic links between PIRB, synaptic plasticity and OD plasticity, and to gain physiological insight into PIRB function at synapses, whole cell microelectrode recordings will be made from neurons in slices of visual cortex or hippocampus. In all specific aims, OD plasticity will be assessed using tract tracing, optical imaging, and immediate early gene induction methods; molecular and biochemical techniques, as well as in situ hybridization, will be used to monitor levels and patterns of gene expression and function. An important implication of these proposed studies is that cortical circuits may retain substantial ability to undergo synaptic change even in adulthood. Thus, if negative regulators of plasticity such as PIRB are present, new therapies may be available for treating developmental learning disorders, as well as adult cognitive loss and stroke. ? ? ?
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