Persistent Kv7.2/7.3 downregulation in the rat pilocarpine model of mesial temporal lobe epilepsy.
Epilepsy Res
; 200: 107296, 2024 Feb.
Article
en En
| MEDLINE
| ID: mdl-38219422
ABSTRACT
Mutations within the Kv7.2 and Kv7.3 genes are well described causes for genetic childhood epilepsies. Knowledge on these channels in acquired focal epilepsy, especially in mesial temporal lobe epilepsy (mTLE), however, is scarce. Here, we used the rat pilocarpine model of drug-resistant mTLE to elucidate both expression and function by quantitative polymerase-chain reaction, immunohistochemistry, and electrophysiology, respectively. We found transcriptional downregulation of Kv7.2 and Kv7.3 as well as reduced Kv7.2 expression in epileptic CA1. Consequences were altered synaptic transmission, hyperexcitability which consisted of epileptiform afterpotentials, and increased susceptibility to acute GABAergic disinhibition. Importantly, blocking Kv7 channels with XE991 increased hyperexcitability in control tissue, but not in chronically epileptic tissue suggesting that the Kv7 deficit had precluded XE991 effects in this tissue. Conversely, XE991 resulted in comparable reduction of the paired-pulse ratio in both experimental groups implying preserved presynaptic Kv7.2 function of Schaffer collateral terminals. Consistent with Kv7.2/7.3 downregulation, the Kv7.3 channel opener ß-hydroxybutyrate failed to mitigate hyperexcitability. Our findings demonstrate that compromised Kv7 function is not only relevant in genetic epilepsy, but also in acquired focal epilepsy. Moreover, they help explain reduced anti-seizure efficacy of Kv7 channel openers in drug-resistant epilepsy.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Epilepsia del Lóbulo Temporal
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Child
/
Humans
Idioma:
En
Revista:
Epilepsy Res
/
Epilepsy res
/
Epilepsy research
Asunto de la revista:
CEREBRO
/
NEUROLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Países Bajos