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bioRxiv · 10.1101/2024.01.24.576980

The alpha4 nicotinic acetylcholine receptor is necessary for the initiation of organophosphate-induced neuronal hyperexcitability

Andrew, P. M.·Feng, W.·Calsbeek, J. J.·Antrobus, S. P.·Cherednychenko, G. A.·MacMahon, J. A.·Bernardino, P. N.·Liu, X.·Harvey, D. J.·Lein, P. J.·Pessah, I.
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Abstract

Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threatening status epilepticus. Significant research effort has been invested investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less effort focused on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination of in vitro and in vivo models. Pharmacological antagonism and genetic deletion of 4, but not 7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that 4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the 4 nAChR subunit warrant further investigation as prophylactic and acute treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.

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Andrew, P. M., Feng, W., Calsbeek, J. J., Antrobus, S. P., Cherednychenko, G. A., MacMahon, J. A., Bernardino, P. N., Liu, X., Harvey, D. J., Lein, P. J., Pessah, I.. 2024-01-26. The alpha4 nicotinic acetylcholine receptor is necessary for the initiation of organophosphate-induced neuronal hyperexcitability. https://doi.org/10.1101/2024.01.24.576980

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