Limited contribution of the lactate receptor HCAR1 to exercise-induced behavioral and hippocampal adaptations

Physical exercise influences hippocampal function and behavior, and lactate has emerged as a candidate signaling molecule linking metabolic activity to neuroplasticity. One proposed mediator is the hydroxycarboxylic acid receptor 1 (HCAR1), but its contribution to behavioral and hippocampal adaptations to exercise remains unclear. We combined studies of HCAR1 knockout (KO) mice with analyses of human postmortem hippocampal tissue to assess whether HCAR1 is required for behavioral or synaptic responses to exercise and to characterize its spatial distribution in human hippocampus. Wild-type (WT) and HCAR1 KO mice of either sex underwent a 3-week high-intensity interval treadmill program or sedentary handling. Behavioral responses were assessed using the splash test and three-chamber sociability assay, and dentate gyrus (DG) field recordings evaluated synaptic transmission and excitability. In parallel, HCAR1 expression was quantified in hippocampal tissue from individuals with major depressive disorder (MDD) and non-depressed controls. Exercise reduced grooming and increased locomotion similarly across genotypes, indicating largely preserved behavioral responses in the absence of HCAR1. HCAR1 KO control mice exhibited delayed initiation of social interaction, not observed in exercised mice. Electrophysiology revealed subtle genotype-dependent differences in DG responsiveness following exercise, without major changes in short-term plasticity. In the small available cohort, HCAR1 showed a predominantly perivascular distribution across hippocampal subregions in both MDD and control cases. Together, these findings indicate that HCAR1 is not required for the primary behavioral and synaptic outcomes measured here following exercise, while leaving open a contribution to more specific aspects of hippocampal function under these or other conditions. Significance Statement Exercise-induced increases in brain lactate have been proposed to influence hippocampal plasticity and behavior, in part through activation of the lactate receptor HCAR1. By testing HCAR1 knockout mice across behavioral and hippocampal electrophysiological outcomes, and by characterizing HCAR1 distribution in human hippocampal tissue, we find that loss of HCAR1 does not substantially alter the behavioral measures assessed or the main behavioral responses to exercise. Human hippocampal HCAR1 showed a predominantly perivascular distribution in both MDD cases and controls. These findings suggest that HCAR1 is not broadly required for the exercise-associated outcomes measured here, while leaving open a role under specific physiological or pathological conditions.