HIIT-induced lactate/GPR81 signaling with dual branches converging on ERK1/2 contributes to hippocampal synaptic remodeling and memory improvement

The remodeling of synapses in the hippocampus is intricately linked to processes of learning and memory. Research indicates that high-intensity interval training (HIIT) enhances cognitive functions reliant on the hippocampus in mice, although the specific receptor-mediated molecular pathways involved are not fully elucidated. Lactate, which is produced in significant amounts during HIIT, may function as a signaling agent in the brain through the lactate receptor G protein-coupled receptor 81 (GPR81), classified as a Gi-type G protein-coupled receptor. This investigation focused on the lactate/GPR81 pathway's contribution to synaptic remodeling in the hippocampus induced by HIIT and examined its downstream signaling characteristics. <i>In vivo</i> results demonstrated that HIIT led to an increase in dendritic spine density and presynaptic vesicle density, enhancing learning and memory; however, these structural and cognitive improvements were negated by the knockdown of GPR81 in the hippocampus. <i>In vitro</i> experiments with Neuro-2a (N2a) cells, when treated with a GPR81 agonist alongside an adenyl cyclase (AC) agonist, a phospholipase C (PLC) inhibitor, and an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, revealed that GPR81 activation resulted in elevated ERK1/2 phosphorylation and increased levels of proteins associated with synaptic remodeling. Further pharmacological interventions reinforced a dual downstream signaling mechanism that involves the inhibition of the AC pathway and the activation of the PLC pathway, both of which converge on ERK1/2. Overall, these results suggest that the lactate/GPR81 pathway is essential for the critical aspects of HIIT-induced synaptic remodeling in the hippocampus and the enhancement of memory, supporting a GPR81-dependent dual-branch model that converges on ERK1/2 in a simplified <i>in vitro</i> context.