High frequency oscillations play important roles in development of epileptogenesis/ictogenesis via activation of astroglial signallings

To explore developmental processes of epileptogenesis/ictogenesis and pathophysiology of carbamazepineresistant epilepsy, we determined effects of high-frequency-oscillation (HFO) on glutamatergic tripartite synaptic transmission, astroglial expression of connexin43, and intracellular Erkand Akt-signalling, using genetic rat model (S286L-TG) of autosomal-dominant sleep-related hypermotor epilepsy(ADSHE), which bears rat S286L-mutant Chrna4(corresponding to human S284L-mutant CHRNA4). Artificial physiological ripple-and pathological fast-ripple-burst stimulations use-dependently increased L-glutamate release through connexin43containing hemichannels by enhancing Erk-signalling alone or both ERK-and Akt-signalling together, respectively. Stimulatory effects of HFO-bursts on astroglial L-glutamate release were enhanced by increasing extra cellular K+ levels, Akt-and Erk-signalling-dependently. HFO-bursts also activated connexin43 expression and Akt-and Erk-signallings use-dependently. Extracellular pH elevation enhanced HFO-burst-evoked astroglial L glutamate release, which was suppressed by therapeutically-relevant concentration of zonisamide via possible carbonic-anhydrase inhibition, but not by that of carbamazepine. Unexpectedly, these responses of S286L-TG to HFO-bursts were almost equal to those of wild-type astrocytes. These results indicated that candidate pathomechanism/pathophysiology of carbamazepine-resistant ADSHE, which enhanced HFO-bursts in S286L-TG neurons may contribute to epileptogenesis/ictogenesis development via activation of connexin43-associated astroglial transmission, which was directly unaffected by mutation, and induced through activated Erksignalling, followed by Akt-signalling. Therefore, suppression of overexpressed Erk-signalling probably prevents ADSHE onset via indirect inhibition of mutant CHRNA4-associated pathomechanistic developments.

Automated summary

In this study, we investigated the effects of high-frequency oscillation (HFO) on synaptic transmission, astroglial expression, and intracellular signaling in a rat model of carbamazepine-resistant epilepsy. We found that HFO increased glutamate release and activated signaling pathways in astrocytes. These findings suggest that HFO may contribute to the development of epilepsy by enhancing astroglial transmission and signaling activation.