Acetylcholine (ACh) is a neurotransmitter widely distributed throughout the central and peripheral nervous systems of vertebrates and invertebrates. In the mammalian central nervous system the predominant physiological effect of ACh is a slow depolarization mediated by muscarinic receptors (slow mACh potential). Slow postsynaptic potentials may account for the synaptic effects such as facilitation or potentiation may account for the synaptic plasticity that underlies the more complex psychobiological phenomena of learning and memory. Cholinergic synapses, in particular, are thought to be of importance in cortical memory processes; and disruption of cortical cholinergic pathways is involved in the development of certain dementias. In Alzheimer's disease, cholinergic neurons in basal forebrain are involved early and severely in the degenerative process; and the degree of cognitive impairment correlates best with the degree of loss of ACh. The precise ionic mechanisms involved in the slow mACh potential in mammalian neurons are not know. Furthermore, the role of second messengers in mediating the mACh response has not been defined. Compared to detailed knowledge of nicotinic ACh receptors and of heart muscarinic receptors, the present state of neuronal muscarinic mechanisms lags behind. These studies will use an invertebrate preparation, the motoneurons of the lobster cardiac ganglion, one of the few example in invertebrate neurobiology for which there is evidence for slow mACh potentials similar to those in vertebrates. Voltage-clamp techniques will be used to gain insight into the ionic mechanisms and metabolic determinants that underlie the slow mACh 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 mechanism s underlying the slow mACh depolarization in lobster cardiac ganglion motoneurons; (2) to characterize the muscarinic receptor subtypes responsible for the mACh response; (3) to ascertain if biochemical second messengers mediate the slow mACh potential; and (4) to determine the similarities and differences between the action of ACh and the peptide proctolin.
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