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bioRxiv · 10.1101/2020.09.21.306019

Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors

Zapukhliak, O.·Netsyk, O.·Romanov, A.·Maximyuk, O.·Oz, M.·Holmes, G. L.·Krishtal, O.·Isaev, D.
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Abstract

Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we study the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission. Simultaneous CA3 and CA1 field potential recordings were obtained during the perfusion of hippocampal slices with the aCSF containing AMPA, NMDA and GABA receptor antagonists. Under these conditions, recurrent field discharges synchronous between CA3 and CA1 were recorded. Field discharges were blocked by addition of calcium-channel blocker Cd2+ and disappeared in CA1 after a surgical cut between CA3 and CA1. Cholinergic antagonist mecamylamine abolished CA3-CA1 synchronous field discharges, while antagonists of 7 and 4{beta}2 nAChRs - MLA and Dh{beta}E had no effect. Our results suggest that activation of nicotinic acetylcholine receptors is able to sustain CA3-CA1 synchronous epileptiform activity independently from AMPA NMDA and GABA transmission. In addition, mecamylamine but not 7 and 4{beta}2 nAChRs antagonists reduce bicuculline-induced seizure-like activity. The ability of mecamylamine to decrease hippocampal network synchronization might be associated with its therapeutic effects in a wide variety of CNS disorders including addiction, depression and anxiety.

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Zapukhliak, O., Netsyk, O., Romanov, A., Maximyuk, O., Oz, M., Holmes, G. L., Krishtal, O., Isaev, D.. 2020-09-21. Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors. https://doi.org/10.1101/2020.09.21.306019

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