Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin neurons, gamma oscillations, and related behaviors.
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.
Steullet
Pascal
P
Department of Psychiatry, Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1008 Prilly-Lausanne, Switzerland.
Cabungcal
Jan-Harry
JH
Kulak
Anita
A
Kraftsik
Rudolf
R
Chen
Ying
Y
Dalton
Timothy P
TP
Cuenod
Michel
M
Do
Kim Q
KQ
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000221:Adaptation, Ocular / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology*; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D064032:Calbindin 2; D064026:Calbindins; D003214:Conditioning, Classical; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D004569:Electroencephalography / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear; D005247:Feeding Behavior / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency; D005978:Glutathione / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology*; D007395:Interneurons / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism*; D010364:Pattern Recognition, Visual / Q000502:physiology; D012201:Reward; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013037:Spatial Behavior / Q000502:physiology
D064032:Calbindin 2; D064026:Calbindins; D018690:Excitatory Amino Acid Agonists; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D000080242:8-Hydroxy-2'-Deoxyguanosine; C546365:GCLM protein, human; D005721:Glutamate-Cysteine Ligase; D003849:Deoxyguanosine; D005978:Glutathione; D007608:Kainic Acid