Abstract: Aerobic exercise facilitates synaptic plasticity, thereby improving cognitive functions such as learning and memory. The 5-hydroxytryptamine system has been indicated in these processes. 5-Hydroxytryptamine type 3 receptors are necessary for exercise-induced hippocampal neurogenesis. Some antipsychotic drugs with 5-hydroxytryptamine type 3 receptor antagonistic properties may impede the amelioration of cognitive impairment and hippocampal plasticity induced by exercise. However, the mechanisms underlying the facilitation of synaptic plasticity by aerobic exercise have not yet been elucidated. In this study, we found that 5-hydroxytryptamine type 3 receptors played an important role in aerobic exercise–mediated improvement of hippocampal-dependent spatial and exploratory memory in mice. While 5-hydroxytryptamine type 3 receptors did not affect baseline neurogenesis in the hippocampal dentate gyrus, 5-hydroxytryptamine type 3 receptors were required for aerobic exercise–induced neurogenesis and astrocyte proliferation in this region. In addition, 5-hydroxytryptamine type 3 receptors were crucial for maintaining long-term potentiation in the CA1, dentate gyrus, and CA3 regions of the hippocampus. The long-term potentiation changes induced by aerobic exercise in sub-regions of the hippocampus were heterogeneous: 5-hydroxytryptamine type 3 receptors were essential for aerobic exercise to enhance long-term potentiation in the CA3, but not the CA1 or dentate gyrus, regions of the hippocampus. Furthermore, aerobic exercise up-regulated 5-hydroxytryptamine type 3 receptor expression and increased brain-derived neurotrophic factor release in the hippocampus in a 5-hydroxytryptamine type 3 receptor–dependent manner. These results suggest that aerobic exercise increases hippocampal dentate gyrus neurogenesis and astrocyte proliferation via the up-regulation of 5-hydroxytryptamine type 3 receptors, leading to more brain-derived neurotrophic factor production and release from these cells, which results in long-term potentiation facilitation in the hippocampal CA3 region and help improve memory. Our findings provide insight into the mechanisms by which physical activity enhances memory and may have implications for improving memory through modulating 5-hydroxytryptamine type 3 receptor.

Key words: 5-hydroxytryptamine, 5-hydroxytryptamine type 3 receptor, aerobic exercise, brain-derived neurotrophic factor, exploratory memory, hippocampus, long-term potentiation, neurogenesis, neuroglia proliferation, spatial memory