Temporal lobe epilepsy (TLE) is the most common type of drug‐resistant epilepsy in adults, yet further mechanistic understanding is still needed. Lactate is mass‐produced during seizures and serves as epileptic fuel afterward, while it also acts as an inhibitory molecule by activating its receptor, hydroxycarboxylic acid receptor 1 (HCAR1). This study is aimed at clarifying the balance between lactate′s role in fueling or inhibiting seizures in patients and animal models with TLE. Lactate was measured in the hippocampus with magnetic resonance spectroscopy (MRS). The expression of lactate dehydrogenase (LDH), monocarboxylate transporter 4 (MCT4), and HCAR1 was quantified with immunostaining and immunoblotting. shRNA and pharmacological manipulation were used to modulate the function of MCT4 or HCAR1 in in vitro and in vivo recording. Results showed that lactate was accumulated in the hippocampal lesions of TLE patients, attributing to the increased lactate catalytic activity of astrocytic LDH. The expressional level of MCT4, which mediated the transmembrane lactate transportation in astrocytes, was increased, whereas inhibition of MCT4 decreased the excitatory synaptic transmission and knockdown of astrocytic Mct4 ameliorated seizure activities in TLE mice. HCAR1 was increased in the hippocampal lesions, and activation of lactate‐HCAR1 signaling attenuated seizure activities in TLE mice. Additionally, the alteration in lactate homeostasis was correlated with seizure frequency in TLE patients and could be modulated by ketogenic diet in TLE mice. These data suggest that the inhibitory signaling effect of lactate is outweighed by its fueling role in TLE. Precisely targeting MCT4 or HCAR1 could be effective antiepileptic strategies.
Song et al. (Thu,) studied this question.