Cannabidiol attenuates behavioral impairments and deficits in parvalbumin interneurons and their perineuronal nets induced by adolescent stress in adult mice.

Adolescence is a critical period for the development of neural circuits, and exposure to stressors during this stage constitutes a risk factor for psychiatric disorders. Previous studies have shown that adolescent stress in rodents leads to behavioral alterations and functional loss of parvalbumin-containing GABAergic (PV+) interneurons and their perineuronal nets (PNNs) in the medial prefrontal cortex (mPFC) and ventral hippocampus (vHip). Although less explored, somatostatin-expressing (SST+) interneurons may also be impaired. Given the reported anti-stress effects of cannabidiol (CBD) in adult rodents, we investigated whether CBD attenuates adolescent stress-induced alterations. Male C57BL/6 J mice were exposed to footshock stress from postnatal day (PND) 31-40 and subsequently received CBD (30 mg/kg, i.p.) for ten days (PND 41-50). After a 15-day drug-free period, animals started being evaluated in adulthood using behavioral assays for anxiety (elevated plus maze, light-dark box), sociability (social interaction), social memory (social discrimination), and cognition (novel object recognition). Adolescent stress impaired social discrimination and object recognition memory, and CBD attenuated these deficits, while sociability and anxiety-like behavior remained unaffected. Consistent with the behavioral findings, stressed animals exhibited reductions in PV+, PNN+, and PV+/PNN+ cells in the mPFC and vHip, as well as a less marked reduction in SST+ cells in the vHip, and CBD attenuated these stress-induced cellular alterations. Our findings suggest that CBD may attenuate behavioral and molecular alterations associated with adolescent stress exposure, particularly those involving PV+ interneurons and their PNNs, highlighting its potential to mitigate stress-induced deficits.