Acetylcholine (ACh) is a neurotransmitter widely distributed throughout the mammalian central and peripheral nervous systems. In the central nervous system the predominant physiological effect of ACh is a slow depolarization mediated by muscarinic receptors (slow m-ACh potential). Slow postsynaptic potentials (psps) may underlie some of the long-term changes in the nervous system. Long-lasting synaptic effects such as facilitation or potentiation may account for the synaptic plasticity that underlies the more complex psychobiological phenomena of learning and memory. Thus, better insight into mechanisms of specific slow psps may lead to better general understanding of synaptic plasticity and neuronal integration. Cholinergic synapses, in particular, are thought to be of prime importance in cortical memory processes, and disruption of cortical cholinergic pathways is involved in the development of certain dementias. A prevailing hypothesis of the pathogenesis of Alzheimer's disease is that the primary pathology is degeneration of a discreet group of cholinergic neurons in the basal forebrain. Because these neurons are the sole source of cholinergic afferents to the entire cortex, their loss leads to widespread cholinergic denervation of the cortex. The precise ionic mechanisms involved in the slow m-ACh potential in mammalian neurons are not known. Furthermore, the role of second messengers in mediating the m-ACh response has not been defined. Thus, compared with the detailed knowledge of nicotinic ACh receptors, the present state of knowledge of neuronal muscarinic ACh receptors lags far behind. These studies will use an in vitro system, sympathetic neurons in tissue culture. Voltage-clamp and patch-clamp techniques will be used to gain insight into the ionic mechanisms and the metabolic determinants that underlie the slow m-ACh response. Experiments will focus on specific ion conductance mechanisms and how they are controlled by biochemical second messengers.
The specific aims are: 1) to establish the ionic mechanisms underlying the slow m-ACh depolarization in rat sympathetic neurons in tissue culture; 2) to determine the pharmacological sensitivity of the m-ACh response to various muscarinic agonists and antagonists; and 3) to ascertain if biochemical second messengers mediate the slow m-ACh potential.
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