Adolescent stress impairs parvalbumin interneurons and their associated perineuronal nets: protective effects of microglia-modulating minocycline treatment

Adolescence is a critical period of brain maturation during which exposure to stress can lead to long-lasting behavioral and neurobiological alterations linked to increased vulnerability to psychiatric disorders. Here, we investigated whether minocycline, a tetracycline antibiotic that modulates microglial activity, could prevent or attenuate the long-term effects of adolescent stress on behavior, parvalbumin (PV)-expressing (+) interneurons (PVIs), perineuronal nets (PNNs), and microglia in adulthood. Male mice were exposed to a 10-day footshock stress protocol during adolescence (postnatal days 31–40) and treated with minocycline (30 mg/kg; i.p.) either during or after stress exposure. Behavioral assessments in adulthood revealed that adolescent stress impaired sociability, social memory, and object recognition memory, which were attenuated by minocycline treatment during or after adolescent stress exposure. Stress also reduced the number of PV+, PNN+, and PV+/PNN+ cells in the prefrontal cortex (PFC) and ventral hippocampus (vHip). These effects were prevented by minocycline administration at both time points. No significant long-lasting changes were observed in microglial number, density, or spatial distribution in either region. However, minocycline treatment modulated microglial morphology in a region- and timing-dependent manner, with increased microglial area observed in the PFC and subtle alterations in circularity in the vHip. These findings suggest that adolescent stress induces enduring impairments in PVIs and behavior, possibly through transient microglial intervention and PNN degradation. Minocycline treatment during or after stress was effective in preventing these changes, supporting its potential as a therapeutic strategy to mitigate the long-term consequences of adolescent stress and to reduce vulnerability to stress-related psychiatric disorders.