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

## TL;DR

HIIT improves memory by triggering a lactate-GPR81 signaling pathway that enhances synaptic remodeling in the hippocampus.

## Contribution

The study identifies a dual-branch GPR81-mediated signaling pathway converging on ERK1/2 that underlies HIIT-induced synaptic remodeling and memory improvement.

## Key findings

- HIIT increases dendritic spine and presynaptic vesicle density in the hippocampus, enhancing memory.
- GPR81 knockdown in the hippocampus negates the synaptic and cognitive benefits of HIIT.
- GPR81 activation elevates ERK1/2 phosphorylation and synaptic plasticity-related proteins like SYN and BDNF.

## Abstract

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. In vivo 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. In vitro 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 in vitro context.

HIIT elevates blood and cerebral lactate levels via anaerobic muscle metabolism. Following the increase in lactate by HIIT, the lactate receptor GPR81 contributes to ERK1/2 activation via AC-RAP1 and PLC-PKC pathways. This pathway promotes the expression of selected synaptic plasticity-related proteins (e.g., SYN and BDNF) and thereby supports improved learning and memory.Diagram illustrating the role of high-intensity interval training (HIIT) in learning and memory. A mouse receives GPR81 knockdown. Lactate is transferred from muscle to the brain via vessels. In the hippocampus, lactate is metabolized involving astrocytes and neurons, regulated by proteins like PKA, RAP1, ERK1/2, and others, leading to synaptic remodeling and plasticity-related protein synthesis. Pathways show roles of MCT1, MCT4, BBB, and GPR81 in lactate transport.

HIIT elevates blood and cerebral lactate levels via anaerobic muscle metabolism. Following the increase in lactate by HIIT, the lactate receptor GPR81 contributes to ERK1/2 activation via AC-RAP1 and PLC-PKC pathways. This pathway promotes the expression of selected synaptic plasticity-related proteins (e.g., SYN and BDNF) and thereby supports improved learning and memory.