Neuronal nitric oxide synthase contributes to chronic stress-induced depression by suppressing hippocampal neurogenesis.
Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. It is well established that neuronal nitric oxide synthase (nNOS)-derived NO exerts a negative control on the hippocampal neurogenesis. Using genetic and pharmacological methods, we investigated the roles of nNOS in depression induced by chronic mild stress (CMS) in mice. Hippocampal nNOS over-expression was first observed 4 days and remained elevated 21 and 56 days after exposure to CMS. The mice exposed to CMS exhibited behavioral changes typical of depression, and impaired neurogenesis in the hippocampus. The CMS-induced behavioral despair and hippocampal neurogenesis impairment were prevented and reversed in the null mutant mice lacking nNOS gene (nNOS-/-) and in the mice receiving nNOS inhibitor. Disrupting hippocampal neurogenesis blocked the antidepressant effect of nNOS inhibition. Moreover, nNOS-/- mice exhibited antidepressant-like properties. Our findings suggest that nNOS over-expression in the hippocampus is essential for chronic stress-induced depression and inhibiting nNOS signaling in brain may represent a novel approach for the treatment of depressive disorders.
Zhou
Qi-Gang
QG
Department of Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
Hu
Yao
Y
Hua
Yao
Y
Hu
Mei
M
Luo
Chun-Xia
CX
Han
Xiao
X
Zhu
Xin-Jian
XJ
Wang
Bin
B
Xu
Jin-Shu
JS
Zhu
Dong-Ya
DY
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D003863:Depression / Q000209:etiology* / Q000473:pathology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019417:Hindlimb Suspension / Q000379:methods; D006624:Hippocampus / Q000473:pathology*; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000502:physiology*; D013315:Stress, Psychological / Q000150:complications*; D013997:Time Factors; D015215:Zidovudine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007191:Indazoles; D015215:Zidovudine; D052248:Nitric Oxide Synthase Type I; D001973:Bromodeoxyuridine; C080122:7-nitroindazole