Glycolysis regulates neuronal excitability via lactate receptor, HCA1R

Abstract

Abstract Repetitively firing neurons during seizures accelerate glycolysis to meet energy demand, which leads to the accumulation of extracellular glycolytic by-product lactate. Here, we demonstrate that lactate rapidly modulates neuronal excitability in times of metabolic stress via the hydroxycarboxylic acid receptor type 1 (HCA1R) to modify seizure activity. The extracellular lactate concentration, measured by a biosensor, rose quickly during brief and prolonged seizures. In two epilepsy models, mice lacking HCA1R (lactate receptor) were more susceptible to developing seizures. Moreover, HCA1R deficient (knockout) mice developed longer and more severe seizures than wild-type littermates. Lactate perfusion decreased tonic and phasic activity of CA1 pyramidal neurons in genetically encoded calcium indicator 7 imaging experiments. HCA1R agonist 3-chloro-5-hydroxybenzoic acid (3CL-HBA) reduced the activity of CA1 neurons in HCA1R WT but not in knockout mice. In patch-clamp recordings, both lactate and 3CL-HBA hyperpolarized CA1 pyramidal neurons. HCA1R activation reduced the spontaneous excitatory postsynaptic current frequency and altered the paired-pulse ratio of evoked excitatory postsynaptic currents in HCA1R wild-type but not in knockout mice, suggesting it diminished presynaptic release of excitatory neurotransmitters. Overall, our studies demonstrate that excessive neuronal activity accelerates glycolysis to generate lactate, which translocates to the extracellular space to slow neuronal firing and inhibit excitatory transmission via HCA1R. These studies may identify novel anticonvulsant target and seizure termination mechanisms.