Protective Effects of N-Acetylcysteine Against Schizophrenia-Related Behavioral and Parvalbumin Interneuron Deficits...

Adolescent stress has been linked to an increased risk of developing psychiatric disorders, including schizophrenia. Previous findings from our group suggest that adolescent stress causes redox imbalance and functional impairments in parvalbumin (PV) interneurons and their associated perineuronal nets (PNNs) in the ventral hippocampus (vHip). These changes are associated with behavioral abnormalities, vHip hyperactivity, and dopamine system overdrive, mirroring observations in people with schizophrenia. Thus, we hypothesized that the antioxidant N-acetylcysteine (NAC) could mitigate schizophrenia-related alterations induced by adolescent stress in adult rats.

Male Sprague-Dawley rats were subjected to a combination of daily footshock and restraint stress during adolescence [postnatal days (PD) 31-40]. NAC (900 mg/L) was administered through the drinking water either during (PD31-40) or after the adolescent stress (PD51-60). In adulthood (PD63), rats underwent behavioral tests to assess anxiety-like behaviors, social interaction, and cognition. From PD70, in vivo recordings of dopamine neurons in the ventral tegmental area (VTA) and immunostaining of PV, PNNs, and the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-Oxo-dG) in the vHip were performed.

Adolescent stress causes, in adulthood, anxiety-like responses, deficits in sociability and cognitive function, increased VTA dopamine neuron population activity, reduced PV⁺ cells in the vHip, including those surrounded by PNNs, and enhanced expression of 8-Oxo-dG, particularly in PV⁺ cells. NAC treatment, whether administered during or after adolescent stress, significantly attenuated these alterations.

NAC effectively mitigates schizophrenia-related changes induced by adolescent stress and may serve as a pharmacological intervention for prevention and treatment strategies.