Enhancing synaptic plasticity and cognitive function through physical exercise: Mechanisms and therapeutic implications

Physical exercise (PE), as a safe, accessible, and relatively low-cost non-pharmacological intervention, has been increasingly shown to delay cognitive decline, reduce dementia risk, and improve learning, memory, executive function, and emotional regulation. Accumulating preclinical and clinical evidence has indicated that PE promotes synaptic plasticity through coordinated molecular, structural, and electrophysiological adaptations. Among the mechanisms supported by the most consistent evidence are enhanced neurotrophic signaling, particularly the BDNF-related pathway, dendritic spine remodeling, hippocampal long-term potentiation (LTP), and regulation of inflammatory, oxidative, and metabolic processes. PE may also influence synaptic function through peripheral–central communication involving circulating factors and systemic axes, including the muscle–brain, liver–brain, and adipose–brain axes. Different exercise modalities, including aerobic exercise (AE), resistance training (RT), dual-task (DT) exercise, and multimodal interventions, appear to produce partially distinct but complementary effects. In this narrative review, we synthesized evidence from preclinical and clinical studies identified through searches of PubMed, Web of Science, and Google Scholar using predefined terms related to physical exercise, synaptic plasticity, and cognition. We discuss the molecular and signaling mechanisms underlying exercise-induced synaptic adaptations, including neurotrophic, metabolic, inflammatory, and synaptic transmission pathways, as well as structural and electrophysiological changes, and their relationships with cognitive outcomes across different populations. We further examined the potential of individualized exercise prescriptions, long-term interventions, multi-omics approaches, and exercise-based multimodal strategies. Overall, current evidence supports PE as a promising strategy for maintaining cognitive function and promoting brain health, particularly through aerobic exercise, while further adequately powered and long-term studies are needed to establish optimal exercise doses, identify responsive populations, and clarify its disease-specific therapeutic efficacy.