GR/HDAC2/synaptic complexes in hippocampal CA1 mediate the antidepressant effects of magnolol

BACKGROUND: Depression is a multifactorial neuropsychiatric disorder linked to neuroinflammation and epigenetic dysregulation, particularly in histone acetylation. Although magnolol has demonstrated antidepressant-like properties, its precise molecular mechanisms remain unclear. This study aimed to evaluate the antidepressant effects of magnolol and its influence on epigenetic regulation of synaptic plasticity in a chronic unpredictable mild stress (CUMS) mouse model. MATERIAL AND METHODS: C57BL/6 mice subjected to CUMS were treated orally with magnolol. Depressive-like behaviors were assessed using standard behavioral tests. Expression levels of histone deacetylase 2 (HDAC2), synaptic proteins such as neuroligin-1 (NLGN1) and neurexin-1β (NRXN1β), and their associated co-localized puncta were examined. Golgi staining and immunofluorescence were performed to assess dendritic spine density and DCX-positive cell population in the hippocampus. RESULTS: Magnolol treatment alleviated depressive-like behaviors, evidenced by increased sucrose preference and reduced immobility in behavioral assays. It also attenuated hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as shown by normalization of serum corticosterone levels and restoration of glucocorticoid receptor (GR) expression in the hippocampal CA1 region. At the molecular level, magnolol reduces HDAC2 expression, which may be associated with altered histone acetylation, thus upregulation of NLGN1 and NRXN1β, enhancing the formation of pre- and postsynaptic co-localized puncta. Additionally, magnolol promoted hippocampal DCX-positive cell population and synaptogenesis, supporting improvements in structural and functional neuroplasticity. CONCLUSION: Our findings demonstrate the ability of magnolol to modulate histone acetylation and synaptic architecture involved in its antidepressant-like action. These results provide a foundation for further exploration of magnolol-based interventions targeting epigenetic and synaptic mechanisms in depression.