BACKGROUNDChronic stress is widely recognized as a critical factor that impairs synaptic plasticity dependent brain function and behavior, contributing to the onset of depression and anxiety disorders, which subsequently undermine learning and memory processes. Gastrodin (GAS), a prominent bioactive constituent of Gastrodiae Rhizoma exhibiting notable neuroprotective properties, holds significant potential for the prevention and treatment of stress-induced neurological dysfunction. However, the protective effects of GAS on stress-induced synaptic plasticity impairment and the underlying mechanisms have yet to be fully elucidated.OBJECTIVESTo investigate the potential of GAS in protecting synaptic plasticity from chronic stress and its underlying cellular and molecular mechanisms.METHODA chronic stress model was constructed in C57BL/6J mice, and the effects of GAS on synaptic plasticity were examined using Golgi staining and immunohistochemistry. Systematic behavioral analysis was employed to assess the impact of GAS on depressive- and anxiety-like behaviors and cognitive function of mice. Metabolomics, transcriptomics, Western blotting, immunolocalization, enzyme-linked immunosorbent assay, and the administration of signal blockers were utilized to investigate the cellular and molecular pathways via which GAS safeguards synaptic plasticity.RESULTSThe results showed that chronic stress exposure reduces the dendritic arbor complexity, density of dendritic spines, proportion of mushroom spines of hippocampal neurons, as well as disrupts synaptic function, impairs cognitive function and induces depressive-like behaviors. Importantly, impairment of hippocampal synaptic plasticity, anxiety- and depressive-like behaviors, and cognitive decline induced by chronic stress were significantly ameliorated following GAS treatment. Moreover, we identified the cAMP/PKA/CREB signaling in hippocampal neurons as a potential mechanism through which GAS prevents synaptic plasticity impairment from chronic stress exposure. Blockade of cAMP/PKA/CREB signaling abolished the protective effects of GAS on synaptic plasticity of hippocampal neurons and behaviors in stress-exposed mice.CONCLUSIONThis study is the first to identify GAS as a potential natural compound for alleviating stress-induced synaptic plasticity impairment and behavioral dysfunction by activating the cAMP/PKA/CREB signaling pathway in hippocampal neurons, offering a promising strategy for stress-induced neurological disorders.