Seminar : Oxidative stress, a core pathological mechanism contributing to schizophrenia?

Abstract:
Prominent theories on the pathogenesis of schizophrenia include dysregulated dopaminergic system, NMDA receptor hypofunction, neuroinflammation, excessive synaptic pruning, aberrant inhibitory GABAergic neurons. Accumulating evidence also shows a link between oxidative stress and schizophrenia. We have explored the upstream molecular events associated with schizophrenia pathology that cause oxidative stress and their consequences. Based on these studies, we propose an integrative model whereby genetic and environmental risk factors during sensitive developmental periods may perturb either glutamatergic transmission, mitochondria bioenergetics, neuro-immune system, or redox regulation that subsequently initiate vicious feedforward loops between these systems leading to long-lasting oxidative stress and defects of inhibitory parvalbumin neurons, a hallmark of schizophrenia pathology. We have also identified brain regions affected in patients (i.e. prefrontal cortex, ventral hippocampus, thalamic reticular nucleus) that are particularly prone to oxidative stress. Altogether, our studies highlight a central role of oxidative stress among the pathological mechanisms related to schizophrenia and support the relevance of antioxidant-based therapies to prevent this homeostatic dysregulation and mitigate some sensory and cognitive deficits, sleep disturbances, and symptoms.