title: Modulation of cellular excitability in neocortex: muscarinic receptor and second messenger-mediated actions of acetylcholine.
abstract: Muscarinic-type acetylcholine (ACh) receptor are involved in a variety of cortical functions. ACh "activates" neocortex; simultaneously modifying spontaneous subthreshold activity, intrinsic neuronal oscillations and spike discharge modes, and responsiveness to fast (putative glutamatergic) synaptic inputs. However, beyond the general involvement of muscarinic receptors, a mechanistic understanding of integrated cholinergic actions, and interactions with non-cholinergic transmission, is lacking. We have addressed this problem using intracellular recordings from the in vitro auditory neocortex. First, we investigated cholinergic modification of responses to the excitatory amino acid glutamate. ACh, or the muscarinic agonist methacholine, produced a lasting enhancement of glutamate-mediated membrane depolarizations. Muscarinic receptors of the M1 and/or M3 subtype, rather than M2 or nicotinic receptors, mediated this enhancement. Subsequently, we investigated whether second messenger systems contribute to observed muscarinic actions. Activation of protein kinase C with phorbol 12,13-dibutyrate (4 beta-PDBu), enhanced neuronal responses to glutamate. The effect of 4 beta-PDBu was attenuated by the kinase antagonist H7. Finally, we attempted to identify postsynaptic actions of endogenous ACh. Tetanic stimulation of cholinergic afferents elicited voltage-dependent effects, including reduced spike frequency adaptation and reduced slow afterhyperpolarization (sAHP) elicited by transmembrane depolarizing stimuli. These effects were mimicked by methacholine, enhanced by eserine, and antagonized by muscarinic receptor antagonists. These data suggest that cholinergic modulation in neocortex likely involves the integrated actions of diverse mechanisms, primarily gated by muscarinic receptors, and at least partly involving second messenger systems.
authors.affiliation: Department of Neuroscience, University of California, Riverside 92521.
authors.forename: C L
authors.initials: CL
authors.lastname: Cox
authors.forename: R
authors.initials: R
authors.lastname: Metherate
authors.forename: J H
authors.initials: JH
authors.lastname: Ashe
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004594:Electrophysiology; D005971:Glutamates / Q000502:physiology; D018698:Glutamic Acid; D007425:Intracellular Membranes / Q000502:physiology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010277:Parasympathomimetics / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology*; D015290:Second Messenger Systems
chemical_list: D005971:Glutamates; D010277:Parasympathomimetics; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D016210:Methacholine Chloride; D015240:Phorbol 12,13-Dibutyrate; D018698:Glutamic Acid; D000109:Acetylcholine