Excitatory effects of muscarine on septohippocampal neurons: involvement of M3 receptors.

Cholinergic mechanisms in the septohippocampal pathway contribute to several cognitive functions and impaired cholinergic transmission in this pathway may be related to the memory loss and dementia that accompanies normal aging and Alzheimer's disease and behavioral studies suggest that muscarinic mechanisms in the medial septum/diagonal band of Broca (MSDB) may contribute to these functions. The goal of the present study was to begin a characterization of the physiological and pharmacological effects of muscarine on antidromically identified septohippocampal neurons (SHNs). Muscarinic agonists produced a concentration-dependent excitation in >90% of SHNs tested using extracellular recordings in an in vitro rat brain slice preparation. The SHNs excited by muscarine had a broad range of conduction velocities (0.2 to 3.7 m/s; mean: 1.6+/-0.06 m/s; n=110), suggesting involvement of neurons with both slow (possibly cholinergic) and fast (possibly GABAergic) conducting fibers. The muscarine-induced excitations in SHNs were found not to be mediated via M1, M2 or M4 receptors, as they were not blocked by the M1-selective antagonists, pirenzepine or telenzepine or by the M2/M4-selective antagonist, methoctramine. In contrast, the M3-selective antagonist, 4-DAMP-mustard, blocked muscarinic excitations in a majority of SHNs, indicating the presence of M3 as well as non-M3-type responses. McN-A-343, an M1 and M5-selective agonist, excited 33% of neurons tested, confirming involvement of non-M3 receptors (possibly M5) and M3 receptors. Since the cholinergic and GABAergic MSDB neurons together innervate almost every type of hippocampal neuron, the effects of muscarine on SHNs would also have a profound effect on hippocampal circuitry.