title: Neuronal nitric oxide synthase (NOS-I) knockout increases the survival rate of neural cells in the hippocampus independently of BDNF.
abstract: Investigations regarding the regulation of adult neurogenesis, i.e., the generation of new neurons from progenitor cells, have revealed a high degree of complexity. Although the pleiotropic messenger molecule nitric oxide (NO) has been suggested to modulate adult neurogenesis, the evidence is inconclusive due to the presence of different NO synthase isoforms in the brain. We therefore investigated whether stem cell proliferation or survival is altered in mice lacking neuronal nitric oxide synthase (NOS-I) or both endothelial and neuronal NOS (NOS-I/-III double knockout). While proliferation of neural stem cells was only numerically, but not significantly increased in NOS-I knockdown animals, the survival of newly formed neurons was substantially higher in NOS-I-deficient mice. In contrast, NOS-I/-III double knockout had significantly decreased survival rates. QRT-PCR in NOS-I-deficient mice revealed neither NOS-III upregulation compensating for the loss of NOS-I, nor alterations in VEGF levels as found in NOS-III-deficient animals. As changes in BDNF expression or protein levels were observed in the cortex, cerebellum and striatum, but not the hippocampus, the increase in stem cell survival appears not to be due to a BDNF mediated mechanism. Finally, NOS-I containing neurons in the dentate gyrus are rare and not localized close to progenitor cells, rendering direct NO effects on these cells unlikely. In conclusion, we suggest that NO predominantly inhibits the survival of new-born cells, by an indirect mechanism not involving BDNF or VEGF. Together, these results emphasize the important role of the different NOS isoforms with respect to adult neurogenesis.
authors: Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy Josef-Schneider-Str. 11, Julius-Maximilians-University Würzburg, Füchsleinstr. 15, D-97080 Würzburg, Germany.
authors: Sabrina
authors: S
authors: Fritzen
authors: Angelika
authors: A
authors: Schmitt
authors: Katharina
authors: K
authors: Köth
authors: Claudia
authors: C
authors: Sommer
authors: Klaus-Peter
authors: KP
authors: Lesch
authors: Andreas
authors: A
authors: Reif
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013234:Stem Cells / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D001973:Bromodeoxyuridine