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The Journal of Neuroscience, January 7, 2004, 24(1):85-95; doi:10.1523/JNEUROSCI.1574-03.2004
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Development/Plasticity/Repair
Nitric Oxide Is a Physiological Inhibitor of Neurogenesis in the Adult Mouse Subventricular Zone and Olfactory Bulb
Bernardo Moreno-López,
Carmen Romero-Grimaldi,
José Angel Noval,
Maribel Murillo-Carretero,
Esperanza R. Matarredona, and
Carmen Estrada
Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, 11003 Cádiz, Spain
The subventricular zone of the rodent brain retains the capacity of generating new neurons in adulthood. The newly formed neuroblasts migrate rostrally toward the olfactory bulb, where they differentiate as granular and periglomerular interneurons. The reported presence of differentiated neurons expressing the neuronal isoform of nitric oxide synthase (NOS) in the periphery of the neurogenic region and the organization of their varicose axons as a network in which the precursors are immersed raised the hypothesis that endogenous nitric oxide (NO) may participate in the control of neurogenesis in the subventricular zone. Systemic administration of the NOS inhibitors N -nitro-L-arginine methyl ester or 7-nitroindazole to adult mice produced a dose- and time-dependent increase in the number of mitotic cells in the subventricular zone, rostral migratory stream, and olfactory bulb, but not in the dentate gyrus of the hippocampus, without affecting apoptosis. In the subventricular zone, this effect was exerted selectively on a precursor subpopulation expressing nestin but not neuronal or glial cell-specific proteins. In addition, in the olfactory bulb, analysis of maturation markers in the newly generated neurons indicated that chronic NOS inhibition caused a delay in neuronal differentiation. Postmitotic cell survival and migration were not affected when NO production was impaired. Our results suggest that NO, produced by nitrergic neurons in the adult mouse subventricular zone and olfactory bulb, exerts a negative control on the size of the undifferentiated precursor pool and promotes neuronal differentiation.
Key words: adult neurogenesis; neural phenotypes; neural precursor proliferation; neuroblasts; nitric oxide synthase; olfactory bulb; subventricular zone
Received June 24, 2003;
revised September 22, 2003;
accepted October 10, 2003.
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