Suppression of epileptiform activity by lactate through HCA1 and GIRK channel activation in rat subicular pyramidal neurons

Abstract

In the present study, we report a lactate-induced hyperpolarization and reduction of epileptiform activity in subicular weak burst firing and regular firing neurons using patch clamp electrophysiology. We showed the expression of lactate receptor Hydroxycarboxylic acid receptor 1 (HCA1) in the subiculum region using immunohistochemistry and found that the inhibitory effect of lactate is through activation of the same receptor because the suppression of epileptiform activity was mimicked by the HCA1 agonist and blocked by the antagonist of HCA1. Lactate-HCA1 interaction leads to activation of Gi-cAMP signaling which was confirmed by pertussis toxin (PTX) experiments by including it in the recording patch pipette. Furthermore, bath perfusion of gallein with lactate after induction of epileptiform activity confirmed the involvement of Gβγ subunit. We hypothesized that Gβγ subunit might activate G protein-coupled inwardly rectifying K+ (GIRK) channel resulting in the observed hyperpolarization with lactate since GIRK channels have been implicated in epilepsy. Using tertiapin-Q (GIRK current blocker) in current-clamp and voltage-clamp experiments validated the activation of GIRK channel by lactate in mediating the inhibition of epileptiform activity. Our findings also suggest that the lactate-induced effect is modulated by the level of cAMP in the cells as treatment with forskolin removed the inhibitory effect of lactate. In conclusion, ours is the first report proposing interaction of lactate with subicular neurons to suppress epileptiform activity through activation of HCA1 and GIRK channel. Our findings suggest future work in exploring the use of lactate as a therapeutic agent in epilepsy research, besides exploring other ion channel targets of lactate.