Abstract
Epilepsy affects millions globally with a significant portion exhibiting pharmacoresistance. Abnormal neuronal activity elevates brain lactate levels, which prompted the exploration of its receptor, the hydroxycarboxylic acid receptor 1 (HCAR1) known to downmodulate neuronal activity in physiological conditions. This study revealed that HCAR1-deficient mice (HCAR1-KO) exhibited lowered seizure thresholds, and increased severity and duration compared to wild-type mice. Hippocampal and whole-brain electrographic seizure analyses revealed increased seizure severity in HCAR1-KO mice, supported by time-frequency analysis. The absence of HCAR1 led to uncontrolled inter-ictal activity in acute hippocampal slices, replicated by lactate dehydrogenase A inhibition indicating that the activation of HCAR1 is closely associated with glycolytic output. However, synthetic HCAR1 agonist administration in an in vivo epilepsy model did not modulate seizures, likely due to endogenous lactate competition. These findings underscore the crucial roles of lactate and HCAR1 in regulating circuit excitability to prevent unregulated neuronal activity and terminate epileptic events.