Inflammation and oxidative stress in psychiatric disorders: Lessons from animal models
With the need for novel targets to treat cognitive deficits and negative symptoms in schizophrenia, identifying translatable biomarkers and proper deficit models has become a key element in preclinical research. Developmental manipulations yielding adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations and to test hypotheses about pathophysiological scenarios. One aspect most models have in common is impaired cortical interneurons, in particular those expressing parvalbumin (PV). We observed that cortical GABA interneurons are affected in adult rats with a neonatal ventral hippocampal lesion (NVHL), DISC1 mice, and other developmental models. Emerging data indicate a role of oxidative stress in schizophrenia, and we explored whether oxidative stress was present in PV cells and whether it could be linked to behavioral and electrophysiological outcomes in the NVHL model. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal PV labeling in NVHL rats, as well as behavioral (prepulse inhibition deficits) and electrophysiological deficits (loss of dopamine modulation of interneuron physiology) present in adult rats with a neonatal hippocampal lesion. Furthermore, NVHL rats exhibited reduced mismatch negativity in auditory evoked potentials, and this deficit was prevented by NAC treatment. These findings suggest that oxidative stress during presymptomatic stages can confer vulnerability for abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention in schizophrenia.