Lecture_8_article - The Journal of Neuroscience, February...

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Neurobiology of Disease Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors Pascal Steullet, 1 * Jan-Harry Cabungcal, 1 * Anita Kulak, 1 * Rudolf Kraftsik, 2 Ying Chen, 3 Timothy P. Dalton, 4 Michel Cuenod, 1 and Kim Q. Do 1 1 Department of Psychiatry, Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1008 Prilly-Lausanne, Switzerland, 2 Department of Cell Biology and Morphology, University of Lausanne, 1005 Lausanne, Switzerland, 3 Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver, Aurora, Colorado 80045, and 4 Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056 Elevated oxidative stress and alteration in antioxidant systems, including glutathione (GSH) decrease, are observed in schizophrenia. Genetic and functional data indicate that impaired GSHsynthesis represents a susceptibility factor for the disorder. Here, we show that a genetically compromised GSH synthesis affects the morphological and functional integrity of hippocampal parvalbumin-immunoreactive (PV-IR) interneurons, known to be affected in schizophrenia. A GSH deficit causes a selective decrease of PV-IR interneurons in CA3 and dendate gyrus (DG) of the ventral but not dorsal hippocampus and a concomitant reduction of b / g oscillations. Impairment of PV-IR interneu- rons emerges at the end of adolescence/early adulthood as oxidative stress increases or cumulates selectively in CA3 and DG of the ventral hippocampus. Such redox dysregulation alters stress and emotion-related behaviors but leaves spatial abilities intact, indicating func- tional disruption of the ventral but not dorsal hippocampus. Thus, a GSH deficit affects PV-IR interneuron’s integrity and neuronal synchrony in a region- and time-specific manner, leading to behavioral phenotypes related to psychiatric disorders. Introduction A hallmark of the pathology of schizophrenia is an alteration of the GABAergic system in prefrontal cortex (PFC) (Lewis et al., 2005) and hippocampus (Zhang and Reynolds, 2002). This in- cludes a reduction of glutamic acid decarboxylase 67 (GAD-67) and the calcium-binding protein parvalbumin (PV) in fast- spiking interneurons (FSIs) (Hashimoto et al., 2003). These FSIs control the output of principal neurons and are necessary for the generation of neuronal synchrony that facilitates information processing and transfer within and between brain regions during cognitive tasks (Bartos et al., 2007; Fries et al., 2007; Sohal et al., 2009). Such oscillations are reduced in schizophrenia patients during impaired cognitive tasks (Cho et al., 2006; Uhlhaas et al., 2008). This suggests that abnormality in synchronized neuronal activity driven by FSI is a core feature of this disorder.
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Lecture_8_article - The Journal of Neuroscience, February...

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