Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors

• Published in: The Journal of neuroscience 2010-02, Vol.30 (7), p.2547-2558
• Main Authors: Steullet, Pascal, Cabungcal, Jan-Harry, Kulak, Anita, Kraftsik, Rudolf, Chen, Ying, Dalton, Timothy P, Cuenod, Michel, Do, Kim Q
• Format: Article
• Language: English
• Subjects: Adaptation, Ocular - physiology; Analysis of Variance; Animals; Animals, Newborn; Behavior, Animal - physiology; Biological Clocks - drug effects; Biological Clocks - physiology; Calbindin 2; Calbindins; Conditioning, Classical; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - metabolism; Electric Stimulation - methods; Electroencephalography - methods; Excitatory Amino Acid Agonists - pharmacology; Exploratory Behavior - physiology; Fear; Feeding Behavior - physiology; Gene Expression Regulation - genetics; Gene Expression Regulation, Developmental - drug effects; Glutamate-Cysteine Ligase - deficiency; Glutathione - deficiency; Hippocampus - cytology; Interneurons - metabolism; Kainic Acid - pharmacology; Male; Maze Learning - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Pathways - physiology; Oxidation-Reduction; Oxidative Stress - physiology; Parvalbumins - metabolism; Pattern Recognition, Visual - physiology; Reward; S100 Calcium Binding Protein G - metabolism; Spatial Behavior - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3857-09.2010

Elevated oxidative stress and alteration in antioxidant systems, including glutathione (GSH) decrease, are observed in schizophrenia. Genetic and functional data indicate that impaired GSH synthesis 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 beta/gamma oscillations. Impairment of PV-IR interneurons 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 functional 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.