Hippocampal neuronal reorganizations, following afferent injury, are well described in rodents and Alzheimer-s Disease patients. The effect of these rearrangements on hippocampal functional integrity is unclear. Over the last few years my laboratory has been particularly interested in the effect of one rearrangement, in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus, after hippocampal cholinergic denervation. Behavioral and biochemical studies in the rat suggest that these fibers are functional; however, changes in post- synaptic cholinergic and adrenergic receptors do not occur. Since the measurement of second messenger systems appears to provide a more sensitive means to assess receptor function, we have investigated the effects of hippocampal sympathetic ingrowth (HSI) on phosphoinositol (PI) hydrolysis. Preliminary data has revealed that maximal carbachol stimulated PI hydrolysis is enhanced by HSI, with no effects observed employing maximal norepinephrine stimulation. The experiments in this proposal will begin to explore these findings, as well as assess the generality of the effect of neuronal reorganizations on PI hydrolysis.
Specific Aim 1 will establish the time course of the effect of HSI on cholinergic stimulated PI hydrolysis by sacrificing animals at different time intervals after HSI induction and assessing maximal carbachol stimulated PI hydrolysis.
Specific Aim 2 will define the biochemical mechanisms through which HSI mediates its effect on PI hydrolysis by assessing the effects of various cholinergic and adrenergic, agonist and antagonist, potassium concentration, excitatory amino acids, nerve growth factor and phorbol esters on PI hydrolysis in the presence or absence of HSI.
Specific Aim 3 will investigate the effect of cortical sympathetic ingrowth on PI hydrolysis in a manner similar to Specific Aim 1 and 2. Finally, Specific Aim 4 will examine the effect of other hippocampal neuronal reorganization,s which occur after entorhinal cortex lesions, on PI hydrolysis by assessing PI hydrolysis at various times after lesioning the presence of excitatory amino acids and/or their analogs, or cholinergic and adrenergic, agonist and antagonist. Since many of the neuronal reorganizations which we plan to study have been described in Alzheimer's Disease, the results may provide insights into how neuronal plasticity alters brain biochemistry in this disorder.
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