Schizophrenia is a severe psychiatric disorder affecting 1% of the world’s population, leading to high human, social and economic burdens. Understanding how the interaction of gene and environment risk factors during neurodevelopment leads to cognitive, affective and social impairment is a central challenge in schizophrenia pathophysiology. I will discuss how these risk factors converge on a hub composed of NMDA-receptor hypofunction, neuroinflammation and redox imbalance/oxidative stress, leading to structural and functional dysconnectivity. Based on oxidative stress markers and genetic associations in patients, this hypothesis received support from a glutathione deficit preclinical model (gclm -/-mice), reproducing numerous schizophrenia phenotypes including NMDA receptor hypofunction, inflammation, impaired parvalbumine fast-spiking GABA interneurons (PVI), myelination, neural synchronization and behavioral anomalies. This model also highlights childhood and peripuberty as critical periods of high vulnerability for environmental adverse insults. Indeed, additional oxidative challenges in juvenile and peripubertal ages, but not in adult gclm-/- mice, lead to severe and permanent PVI impairment. Regulation of redox state in PVI also balances plasticity and stability across cortical development, through delaying and/or keeping critical periods of plasticity open-ended. Moreover, long range connections may also be affected by redox dysregulation during development: gclm-/- mice present myelin marker deficits in the prefrontal cortex at peripuberty, involving the Fyn kinase pathway dysregulation, which lead to decreased oligodendrocyte proliferation. Most importantly, the antioxidant and GSH precursor N-acetyl-cysteine (NAC), prevents the morphological, biochemical, physiological and behavioral alterations described above. A translational approach towards prevention attempts to modify the disease course by redox modulators will be presented.
Research And Development
Medical Laboratory Technician25%
Manufacturer - Other25%