Attenuating M-current suppression in vivo by a mutant Kcnq2 gene knock-in reduces seizure burden, and prevents status epilepticus-induced neuronal death and epileptogenesis
| Autor: | Derek L. Greene, Naoto Hoshi, Anastasia Kosenko |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
kainate
0301 basic medicine Male medicine.medical_treatment Neurodegenerative Pharmacology Inbred C57BL Epileptogenesis Transgenic Membrane Potentials Epilepsy Mice 0302 clinical medicine Status Epilepticus Kcnq2 2.1 Biological and endogenous factors Aetiology Cells Cultured Cerebral Cortex Neurons Cultured Kv7.2 Glutamate Decarboxylase Pilocarpine Neurology Neurological Anticonvulsants Female medicine.symptom Proto-Oncogene Proteins c-fos medicine.drug Cells 1.1 Normal biological development and functioning Clinical Sciences Mice Transgenic Status epilepticus Muscarinic Agonists Muscarinic agonist Article 03 medical and health sciences Underpinning research Neurotransmitter receptor Gene knockin medicine Animals KCNQ2 Potassium Channel Neurology & Neurosurgery Animal business.industry Neurosciences medicine.disease Brain Disorders Mice Inbred C57BL Disease Models Animal 030104 developmental biology Anticonvulsant Gene Expression Regulation Disease Models Mutation Neurology (clinical) business 030217 neurology & neurosurgery |
| Zdroj: | Epilepsia, vol 59, iss 10 |
| Popis: | OBJECTIVES The M-current is a low-threshold voltage-gated potassium current generated by Kv7 subunits that regulates neural excitation. It is important to note that M-current suppression, induced by activation of Gq-coupled neurotransmitter receptors, can dynamically regulate the threshold of action-potential firing and firing frequency. Here we sought to directly examine whether M-current suppression is involved in seizures and epileptogenesis. METHODS Kv7.2 knock-in mice lacking the key protein kinase C (PKC) phosphorylation acceptor site for M-current suppression were generated by introducing an alanine substitution at serine residue 559 of mouse Kv7.2, mKv7.2(S559A). Basic electrophysiologic properties of the M-current between wild-type and Kv7.2(S559A) knock-in mice were analyzed in primary cultured neurons. Homozygous Kv7.2(S559A) knock-in mice were used to evaluate the protective effect of mutant Kv7.2 channel against chemoconvulsant-induced seizures. In addition, pilocarpine-induced neuronal damage and spontaneously recurrent seizures were evaluated after equivalent chemoconvulsant-induced status epilepticus was achieved by coadministration of the M-current-specific channel inhibitor, XE991. RESULT Neurons from Kv7.2(S559A) knock-in mice showed normal basal M-currents. Knock-in mice displayed reduced M-current suppression when challenged by a muscarinic agonist, oxotremorine-M. Kv7.2(S559A) mice were resistant to chemoconvulsant-induced seizures with no mortality. Administration of XE991 transiently exacerbated seizures in knock-in mice equivalent to those of wild-type mice. Valproate, which disrupts neurotransmitter-induced M-current suppression, showed no additional anticonvulsant effect in Kv7.2(S559A) mice. After experiencing status epilepticus, Kv7.2(S559A) knock-in mice did not show seizure-induced cell death or spontaneous recurring seizures. SIGNIFICANCE This study provides evidence that neurotransmitter-induced suppression of M-current generated by Kv7.2-containing channels exacerbates behavioral seizures. In addition, prompt recovery of M-current after status epilepticus prevents subsequent neuronal death and the development of spontaneously recurrent seizures. Therefore, prompt restoration of M-current activity may have a therapeutic benefit for epilepsy. |
| Databáze: | OpenAIRE |
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