Glucose Deficiency Elevates Acid-Sensing Ion Channel 2a Expression and Increases Seizure Susceptibility in Temporal Lobe Epilepsy

Abstract

Abstract Brain hypometabolism is a common epilepsy-related finding in both patients and animal models. Fluorodeoxyglucose positron emission tomography studies have shown that recurrent seizures lead to reduced glucose metabolism in certain brain regions, but no studies have definitively determined whether this induces epileptogenesis. There is evidence that acid-sensing ion channel 2a (ASIC2a) affects epilepsy susceptibility. Transcription factor CP2 (TFCP2) regulates ASIC2a expression. We report that suppressed TFCP2 expression and elevated ASIC2a expression were associated with glucose hypometabolism in the hippocampi of humans with epilepsy and of rat epilepsy model brains. In cultured PC12 cells, we determined that glucose deficiency led to TFCP2 downregulating ASIC2a. Moreover, electrophysiological recordings from cultured rat hippocampal slices showed that ASIC2a overexpression resulted in more action potentials in CA1 pyramidal neurons and increased seizure susceptibility. Our findings suggest that hippocampal glucose hypometabolism elevates ASIC2a expression by suppressing TFCP2 expression, which further enhances the intrinsic excitability of CA1 pyramidal neurons and increases seizure susceptibility in patients with temporal lobe epilepsy.