Exercise-induced neuronal effects and the 5-HT3 receptor

Fourteen subtypes of the serotonin (5-hydroxytryptamine, 5-HT) receptor have been delineated, and these subtypes are assigned to seven 5-HT receptor subfamilies (5-HT1-7).  Among the 5-HT receptor subfamilies, the 5-HT type 3 (5-HT3) receptor is the only ionotropic receptor. Previous studies have reported abundant expression of the 5-HT3 receptor in the hippocampus, and the involvement in the mood and memory. However, possible roles of the 5-HT3 receptor in hippocampal neurogenesis remains unknown. We performed immunohistochemical analyses of adult hippocampal neurogenesis in the 5-HT3A receptor-deficient mice ( htr3a-/- mice). We found that basal cell proliferation and neurogenesis in the hippocampal dentate gyrus of htr3a-/- mice were normal. Exercise is known to increase hippocampal neurogenesis, cause antidepressant effects and enhance learning ability. Immunohistochemical and behavioral analyses of htr3a-/- mice revealed that a lack of the 5-HT3 receptor led to a blockade of the exercise-induced neurogenesis in the hippocampus and antidepressant effects, but not of enhanced learning ability. Moreover, we have shown that the 5-HT3 receptor agonist enhanced cell proliferation in the hippocampal dentate gyrus. Our results indicate that the 5-HT3 receptor is indispensable for increased hippocampal neurogenesis and antidepressant effects induced by exercise.