The Journal of Neurophysiology Vol. 85 No. 3 March 2001, pp. 1197-1205
Copyright ©2001 by the American Physiological Society

Serine/Threonine Protein Phosphatases and Synaptic Inhibition Regulate the Expression of Cholinergic-Dependent Plateau Potentials

 ¹Neuroscience Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1; and  ²Departments of Paediatrics, Anatomy, and Cell Biology, Clinical Trials Group, Canadian Paediatric Epilepsy Network, Queen's University, Kingston, Ontario K7L 3N6, Canada

Fraser, Douglas D., Daniel Doll, and Brian A. MacVicar. Serine/Threonine Protein Phosphatases and Synaptic Inhibition Regulate the Expression of Cholinergic-Dependent Plateau Potentials. J. Neurophysiol. 85: 1197-1205, 2001. We previously identified cholinergic-dependent plateau potentials (PPs) in CA1 pyramidal neurons that were intrinsically generated by interplay between voltage-gated calcium entry and a Ca²⁺-activated nonselective cation conductance. In the present study, we examined both the second-messenger pathway and the role of synaptic inhibition in the expression of PPs. The stimulation of m1/m3 cholinergic receptor subtypes and G-proteins were critical for activating PPs because selective receptor antagonists (pirenzepine, hexahydro-sila-difenidol hydrochloride, 4-diphenylacetoxy-N-methylpiperidine methiodide) and intracellular guanosine-5'-O-(2-thiodiphosphate) prevented PP generation in carbachol. Intense synaptic stimulation occasionally activated PPs in the presence of oxytremorine M, a cholinergic agonist with preference for m1/m3 receptors. PPs were consistently activated by synaptic stimulation only when oxytremorine M was combined with antagonists at both GABA_A and GABA_B receptors. These latter data indicate an important role for synaptic inhibition in preventing PP generation. Both intrinsically generated and synaptically activated PPs could not be elicited following inhibition of serine/threonine protein phosphatases by calyculin A, okadaic acid, or microcystin-L, suggesting that muscarinic-induced dephosphorylation is necessary for PP generation. PP genesis was also inhibited following irreversible thiophosphorylation by intracellular perfusion with ATP--S. These data indicate that the expression of cholinergic-dependent PPs requires protein phosphatase-induced dephosphorylation via G-protein-linked m1/m3 receptor(s). Moreover, synaptic inhibition via both GABA_A and GABA_B receptors normally prevents the synaptic activation of PPs. Understanding the regulation of PPs should provide clues to the role of this regenerative potential in both normal activity and pathophysiological processes such as epilepsy.