Background and Purpose Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5‐HT) transporter (SERT) in mediating these effects. Experimental Approach Hippocampal long‐term potentiation (LTP) and neurogenesis were measured in standard‐housed and exercising (wheel running) wild‐type (WT) and SERT heterozygous (HET) mice. We also assessed hippocampal‐dependent cognition using the Morris water maze (MWM) and a spatial pattern separation touchscreen task. Key Results SERT HET mice had impaired hippocampal LTP regardless of the housing conditions. Exercise increased hippocampal neurogenesis in WT mice. However, this was not observed in SERT HET animals, even though both genotypes used the running wheels to a similar extent. We also found that standard‐housed SERT HET mice displayed altered cognitive flexibility than WT littermate controls in the MWM reversal learning task. However, SERT HET mice no longer exhibited this phenotype after exercise. Cognitive changes, specific to SERT HET mice in the exercise condition, were also revealed on the touchscreen spatial pattern separation task, especially when the cognitive pattern separation load was at its highest. Conclusions and Implications Our study is the first evidence of reduced hippocampal LTP in SERT HET mice. We also show that functional SERT is required for exercise‐induced increase in adult neurogenesis. Paradoxically, exercise had a negative impact on hippocampal‐dependent cognitive tasks, especially in SERT HET mice. Taken together, our results suggest unique complex interactions between exercise and altered 5‐HT homeostasis.

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