Minocycline modulates hippocampal BDNF-PSD95 and glial inflammatory protein signaling to alleviate chronic restraint stress-induced depressive- and anxiety-like behaviors.

Chronic restraint stress (CRS) is a widely used experimental model for investigating the neurobiological mechanisms underlying stress-related mood disorders, including depression and anxiety. Increasing evidence suggests that neuroinflammation and impaired synaptic plasticity contribute to the development of these behavioral abnormalities; however, the underlying molecular pathways remain incompletely understood. In the present study, we investigated the effects of CRS on hippocampal brain-derived neurotrophic factor (BDNF)-postsynaptic density protein 95 (PSD95) signaling and glial inflammatory protein expression and evaluated the therapeutic potential of minocycline. CRS exposure induced depressive- and anxiety-like behaviors, as evidenced by increased immobility in the forced swim and tail suspension tests, reduced sucrose preference, and anxiety-related behavioral deficits. At the molecular level, CRS significantly increased microglial and astrocytic activation while reducing the expression of BDNF and PSD95 in the hippocampus, indicating impaired neurotrophic support and synaptic integrity. Treatment with minocycline markedly attenuated glial activation, restored hippocampal BDNF and PSD95 expression, and improved both depressive- and anxiety-like behaviors. These findings demonstrate that CRS-induced behavioral abnormalities are associated with dysregulation of hippocampal BDNF-PSD95 signaling and enhanced glial inflammatory responses. Furthermore, minocycline exerts neuroprotective and behavioral benefits by modulating glial inflammatory protein signaling and preserving neurotrophic and synaptic plasticity pathways. Collectively, these results highlight the therapeutic potential of minocycline for stress-related mood disorders and identify hippocampal BDNF-PSD95 and glial inflammatory signaling as important targets underlying its beneficial effects.