Prevention and Alleviation of Penicillin-induced Epileptic Discharge by Transient Receptor Potential Vanilloid 4 (TRPV4) Antagonist in Mice: Effects Mediated by Extracellular Glutamate Control

Transient receptor potential vanilloid 4 (TRPV4) channels, expressed in presynaptic membranes and astrocytes, have attracted attention as factors involved in epilepsy. We investigated the role of TRPV4 channels as therapeutic targets for epilepsy. We injected Penicillin G (PG) into the cortex of wild-type (WT) mice or TRPV4 KO mice. We also injected RN 1734, a TRPV4 antagonist, before and after PG injection. We recorded epileptic discharges (EDs) and the concentration of extracellular glutamate in the mice. In WT mice, the glutamate concentration increased after PG injection and EDs occurred. In TRPV4 KO mice, the glutamate concentration and beta-band power of the EDs were lower than that in WT mice. When WT mice were administered RN 1734 prior to PG injection, both the glutamate concentration and spike amplitude at late phase following PG injection were comparable to those in TRPV4 KO mice. However, when RN 1734 was administered after the onset of EDs, the alleviation of EDs lasted for only 10 min, and the glutamate concentration did not decrease. RN 1734 modulated EDs in a timing-dependent manner, with significant effects during ongoing EDs and limited effects following pre-treatment. These results indicate that TRPV4 antagonists modulate glutamate dynamics in an activity-dependent manner.