Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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8-Hydroxy-2'-Deoxyguanosine
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Adaptation, Ocular / physiology
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Analysis of Variance
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Animals
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Animals, Newborn
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Behavior, Animal / physiology*
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Biological Clocks / drug effects
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Biological Clocks / physiology*
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Calbindin 2
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Calbindins
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Conditioning, Classical
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Deoxyguanosine / analogs & derivatives
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Deoxyguanosine / metabolism
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Electric Stimulation / methods
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Electroencephalography / methods
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Excitatory Amino Acid Agonists / pharmacology
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Exploratory Behavior / physiology
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Fear
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Feeding Behavior / physiology
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Gene Expression Regulation / genetics
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Gene Expression Regulation, Developmental / drug effects
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Glutamate-Cysteine Ligase / deficiency
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Glutathione / deficiency
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Hippocampus / cytology*
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Interneurons / metabolism*
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Kainic Acid / pharmacology
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Male
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Maze Learning / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neural Pathways / physiology
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Oxidation-Reduction
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Oxidative Stress / physiology*
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Parvalbumins / metabolism*
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Pattern Recognition, Visual / physiology
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Reward
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S100 Calcium Binding Protein G / metabolism
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Spatial Behavior / physiology
Substances
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Calbindin 2
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Calbindins
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Excitatory Amino Acid Agonists
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Parvalbumins
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S100 Calcium Binding Protein G
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8-Hydroxy-2'-Deoxyguanosine
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GCLM protein, human
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Glutamate-Cysteine Ligase
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Deoxyguanosine
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Glutathione
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Kainic Acid