MAR 18, 2015 10:30 AM PDT

Special Lecturer - Oxidative Stress in Schizophrenia: a Translational Approach

Presented at: Neuroscience
Speaker
  • Professor, Center for Psychiatric Neuroscience, Lausanne University Hospital
    Biography
      Following a career in basic research in chemistry, molecular biology and neurobiology (glutatmate and nitric oxide transmission, neuro Research Institute (Zurich University), I moved towards "bench to bed" research at the Center for Psychiatric Neuroscience (Department of Psychiatry, Lausanne University Hospital). I set up a translational research program aimed at a better understanding of the causes and mechanisms leading to schizophrenia phenotypes in order to develop markers for early diagnosis, new drug targets as well as preventive and therapeutic measures. Building on an innovative hypothesis, I could demonstrate that oxidative stress/redox dysregulation induced, among others, by glutathione (GSH) deficit, may represent a "hub" on which both genetic and environmental risk factors converge during neurodevelopment, leading to the impairment of neural connectivity and synchronization, and to cognitive deficits as observed in patients. These mechanisms have been comprehensively documented in experimental models. Based on these relevant neurobiological data, a precursor of GSH, N administered to chronic patients. This double blind, placebo controlled add trial with NAC showed a net improvement potentials (mismatch negativity), neural synchronization, and produced no side effects. These promising results led a new clinical trial with young patients during their first psychotic episode, paving the way for risk subjects. In addition to my research activities, I serve as director of the Unit of Research in Schizophrenia and director of the Center for Psychiatric Neuroscience, where we also work on professional education and cure of major psychiatric disorders.

    Abstract

    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.


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