Cognitive impairment is a serious health concern in the United States; it accompanies normal aging and dementing disorders such as Alzheimer's, as well as mental illnesses, such as schizophrenia and depression. Basic and clinical studies have long recognized the importance of acetylcholine (ACh) in cognition. The cholinergic muscarinic receptor antagonist, scopolamine, impairs learning and memory in humans and rodents primarily through actions on the brain septohippocampal neurons (SHNs). Acetylcholinesterase inhibitors, although limited in efficacy, are currently the best available treatment for Alzheimer's disease. The cyclic nucleotides, cAMP and cGMP, have also been implicated in learning and memory and certain phosphodiesterase (PDE) inhibitors that prevent cyclic nucleotide hydrolysis are cognitively beneficial and can also reverse scopolamine-induced cognitive deficits. While cAMP is effectively recruited by the stress-related neurotransmitter, CRF, the gaseous neural messenger, nitric oxide (NO) is the primary activator of the cGMP cascade. The SHNs, that give rise to the mnemonically important septohippocampal pathway receive CRF innervation, are endowed with CRF1 receptors and in preliminary electrophysiological studies were activated by CRF and cAMP analogs. Additionally, cholinergic SHNs belong to the unique population of CNS neurons that express the NO synthesizing enzyme. In preliminary studies GABA-type but not cholinergic-type SHNs, were activated by NO donors and cGMP analogs. NO imaging studies and PDE inhibitors also suggested the presence of a constitutive NO/cGMP tone as well as a cAMP tone in this brain region. We hypothesize that: 1) NO released from cholinergic SHNs behaves as an intercellular messenger to activate GABAergic SHNs through activation of the cGMP-kinase cascade and that cGMP actions are terminated primarily by the cGMP-specific PDE9; 2) CRF acting via CRF1 receptors and the cAMP-kinase cascade in cholinergic SHNs indirectly activates GABAergic SHNs through increased ACh release; 3) cAMP actions are terminated primarily by PDE4 and cross-talk between the cyclic nucleotide pathways occurs through dual-substrate PDE2 and possibly through a CRF-induced increase in NO synthesis. The above hypothesis will be tested using electrophysiological, immunohistochemical and NO visualization techniques in rodent brain slices. ? ?
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