Increased neurogenesis in a rat ketamine model of schizophrenia.
BACKGROUND
Growing evidence implicates abnormal neurodevelopment in schizophrenia, which manifests itself, for example, in reduced volume and cellular disarray of the hippocampus. This prompted us to investigate if there are indications of an altered neurodevelopment in this brain region. While neuron birth is largely completed by the end of gestation, granule neurons of the dentate gyrus are generated throughout life, thus offering an opportunity to investigate neurogenesis postnatally.


METHODS
We investigated whether repeated application of subanesthetic doses of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine, which has been shown to mimic model aspects of schizophrenia in animals, affects the hippocampal neurogenesis detected by bromodeoxyuridine incorporation. Cells were identified by immunocytochemistry.


RESULTS
Subanesthetic doses of ketamine applied subchronically enhance neurogenesis in the hippocampal subgranular zone.


CONCLUSIONS
In our animal model of schizophrenia, ketamine may evoke its stimulating effect on neurogenesis via a block of the N-methyl-D-aspartate receptor directly by reducing the c-Fos/c-Jun expression, resulting in a depression of the AP1 transcription factor complex and/or by a reduced nitric oxide production or an enhanced serotonergic activity. The newly formed neurons are not able to overcome the schizophrenia-related loss of parvalbumin expressing neurons and the behavioral abnormalities indicating that their functional integration is crucial.
Keilhoff
Gerburg
G
Institute of Medical Neurobiology, University of Magdeburg, Magdeburg, Germany. gerburg.keilhoff@medizin.uni-magdeburg.de
Bernstein
Hans-Gert
HG
Becker
Axel
A
Grecksch
Gisela
G
Wolf
Gerald
G
D000818:Animals; D000941:Antigens / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000503:physiopathology; D007150:Immunohistochemistry / Q000379:methods; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007649:Ketamine / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000139:chemically induced* / Q000503:physiopathology; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D001973:Bromodeoxyuridine; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D007649:Ketamine; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D010320:Parvalbumins; D010751:Phosphopyruvate Hydratase; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4; C577486:Nes protein, rat