Cyclic GMP is an important second messenger in many tissues including the Central Nervous System. It is the central hypothesis of this proposal that cGMP plays an important role in regulating synaptic efficacy in the developing and mature mammalian visual system and that the actions of cGMP are mediated both by a class of cyclic nucleotide gated cation channels and by cGMP-dependent protein kinases. The overall hypothesis of this proposal will be tested with three specific aims. In the first, the levels of expression and cellular distribution of molecules involved in both cGMP metabolism and cGMP actions will be measured during normal development and in dark-reared animals. The results of these experiments will indicate whether cGMP acts in the same way in all cortical neurons, whether cGMP is used as a messenger at all stages of development and whether patterned visual input alters the cGMP second messenger system. The second specific aim will determine whether cGMP levels in visual cortex are regulated by neural activity by measuring the concentrations of cGMP in cortical slices following treatment with selected neurotransmitter agonists and antagonists. These experiments will focus on glutamate, acetylcholine and noradrenaline because these have been implicated in the regulation of cGMP levels and in visual cortical plasticity. The third specific aim will test directly whether cGMP can modulate membrane properties and synaptic interactions of identified visual cortical neurons. Direct and indirect effects of cGMP on membrane conductances will be measured by recording from cells identified by retrograde transport or antibody labeling. The effects of cGMP on responses to glutamate receptor agonists will be measured to determine whether receptor sensitivity or desensitization is altered. Finally, the ability of cGMP to alter synaptic interactions between cortical neurons will be measured. Using a series of agonists and antagonists selective for cGMP-dependent protein kinases of cyclic nucleotide gated cation channels, experiments will be carried out to determine the pathway by which cGMP exerts its effects. Overall, this project will elucidate the functions of an important second messenger system in visual cortex, particularly the ways in which cGMP can alter the efficacy of synaptic interactions between cortical neurons. The information gained from these experiments will improve understanding of normal information processing and of important developmental abnormalities that affect visual cortex such as amblyopia and strabismus.
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