Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation.
Neuronal nitric oxide synthase, the major nitric oxide synthase isoform in the mammalian brain, is implicated in some developmental processes, including neuronal survival, precursor proliferation and differentiation. However, reports about the role of neuronal nitric oxide synthase in neurogenesis in the adult dentate gyrus are conflicting. Here we show that 5-bromodeoxyuridine-labeled dividing progenitor cells in the dentate gyrus were significantly increased in mice receiving 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, and in null mutant mice lacking neuronal nitric oxide synthase gene (nNOS-/-) 6 h and 4 weeks after 5-bromodeoxyuridine incorporation. The increase in 5-bromodeoxyuridine positive cells in 7-nitroindazole-treated mice was accompanied by activation of cyclic AMP response element binding protein phosphorylation in the dentate gyrus. Pretreatment with N-methyl-D-aspartate receptor antagonist MK-801 fully abolished the effects of 7-nitroindazole on neurogenesis and cyclic AMP response element binding protein phosphorylation. Furthermore, neuronal nitric oxide synthase inhibition significantly enhanced the survival of newborn cells and the number of 5-bromodeoxyuridine positive/NeuN positive cells in the dentate gyrus. These results indicate that neuronal nitric oxide synthase-derived nitric oxide suppresses neurogenesis in the adult dentate gyrus, in which N-methyl-D-aspartate receptor functions and cyclic AMP response element binding protein phosphorylation may be involved.
Zhu
X J
XJ
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, 140 Road Hanzhong, Nanjing, China 210029.
Hua
Y
Y
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, 140 Road Hanzhong, Nanjing, China 210029.
Jiang
J
J
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, 140 Road Hanzhong, Nanjing, China 210029.
Zhou
Q G
QG
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, 140 Road Hanzhong, Nanjing, China 210029.
Luo
C X
CX
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, 140 Road Hanzhong, Nanjing, China 210029.
Han
X
X
Laboratory of Mammalian Genes, Nanjing Medical University, Nanjing, China 210029.
Lu
Y M
YM
Biomolecular Science Center, Burnet College of Biomedical Science, University of Florida, Room 324/BMS, 4000 Central Florida Boulevard, Orlando, FL 32816, USA.
Zhu
D Y
DY
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, 140 Road Hanzhong, Nanjing, China 210029; Laboratory of Mammalian Genes, Nanjing Medical University, Nanjing, China 210029. Electronic address: yxy@njmu.edu.cn.
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D018891:Dentate Gyrus / Q000187:drug effects* / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007191:Indazoles; D009569:Nitric Oxide; D012694:Serine; D016291:Dizocilpine Maleate; D052248:Nitric Oxide Synthase Type I; D001973:Bromodeoxyuridine; C080122:7-nitroindazole