M-current preservation contributes to anticonvulsant effects of valproic acid
Hee Yeon Kay, … , Anastasia Kosenko, Naoto Hoshi
Hee Yeon Kay, … , Anastasia Kosenko, Naoto Hoshi
Published September 8, 2015
Citation Information: J Clin Invest. 2015;125(10):3904-3914. https://doi.org/10.1172/JCI79727.
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Research Article Neuroscience

M-current preservation contributes to anticonvulsant effects of valproic acid

Abstract

Valproic acid (VPA) has been widely used for decades to treat epilepsy; however, its mechanism of action remains poorly understood. Here, we report that the anticonvulsant effects of nonacute VPA treatment involve preservation of the M-current, a low-threshold noninactivating potassium current, during seizures. In a wide variety of neurons, activation of Gq-coupled receptors, such as the m1 muscarinic acetylcholine receptor, suppresses the M-current and induces hyperexcitability. We demonstrated that VPA treatment disrupts muscarinic suppression of the M-current and prevents resultant agonist-induced neuronal hyperexcitability. We also determined that VPA treatment interferes with M-channel signaling by inhibiting palmitoylation of a signaling scaffold protein, AKAP79/150, in cultured neurons. In a kainate-induced murine seizure model, administration of a dose of an M-channel inhibitor that did not affect kainate-induced seizure transiently eliminated the anticonvulsant effects of VPA. Retigabine, an M-channel opener that does not open receptor-suppressed M-channels, provided anticonvulsant effects only when administered prior to seizure induction in control animals. In contrast, treatment of VPA-treated mice with retigabine induced anticonvulsant effects even when administered after seizure induction. Together, these results suggest that receptor-induced M-current suppression plays a role in the pathophysiology of seizures and that preservation of the M-current during seizures has potential as an effective therapeutic strategy.

Authors

Hee Yeon Kay, Derek L. Greene, Seungwoo Kang, Anastasia Kosenko, Naoto Hoshi

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Figure 1

VPA attenuated muscarinic suppression of the M-current and prevented oxo-M–induced hyperexcitability in cultured SCG and hippocampal neurons.

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VPA attenuated muscarinic suppression of the M-current and prevented oxo...
(A) Representative voltage-clamp current traces from SCG neurons (top) and pooled results (bottom) showing M-current suppression by 0.1 μM oxo-M and its disruption by 500 μM VPA pretreatment. Amplitudes of the M-currents are normalized to those at t = 0. Black box indicates presence of 0.1 μM oxo-M. (B) Summary of muscarinic suppression of the M-current at t = 1 min including results shown in A. Muscarinic suppression is attenuated by 500 μM VPA but not by 500 μM valeric acid, 100 μM vigabatrin, or 100 μM phenytoin. **P < 0.01 using Kruskal-Wallis one-way ANOVA followed by Dunn’s multiple comparisons test. Numbers above bars represent n values. (C) Current clamp traces showing action potential firing in response to 50 pA current injection. Traces from VPA-nontreated (top), 500 μM VPA–treated (middle), and 500 μM valeric acid–treated (bottom) hippocampal neurons are shown. Control, presence of 1 μM oxo-M, or presence of 20 μM XE991. (D and E) Input-excitation relationships from hippocampal neurons before (open circle) and after application of oxo-M (filled circle) from nontreated neurons (D) or 500 μM VPA–treated neurons (E). (F) Summary of neural firing by 50 pA current injection shown in C–E. **P < 0.01 and ***P < 0.001 using repeated measures one-way ANOVA followed by Tukey’s multiple comparisons test. Error bars show ± SEM.