Differential effect of endothelial nitric oxide synthase (NOS-III) on the regulation of adult neurogenesis and behaviour

Abstract

Although it has been postulated that adult neurogenesis, i.e. the generation of functional neurons from progenitor cells in the mammalian brain, is involved in both the pathogenesis of depressive disorders and the therapeutic effect of antidepressant drugs, its regulation is still poorly understood. Nitric oxide, a gaseous messenger molecule, represents a possible modulating agent as it is involved in learning and memory formation as well as synapto- and morphogenesis. Here we investigated whether adult neurogenesis is altered in mice lacking endothelial nitric oxide synthase (NOS-III). Compared to wild-type littermates, NOS-III-deficient mice showed a significant reduction in neuronal progenitor cell proliferation in the dentate gyrus, suggesting a role for NOS-III in the stimulation of neuroneogenesis. NeuN, beta-III-tubulin and GFAP double-immunolabelling demonstrated that proliferating progenitor cells differentiate preferentially into neurons but not into astrocytes. However, when the survival rate of newly formed cells was examined no difference between wild-type and NOS-III knockout mice was found, suggesting that NOS-III selectively exerts its effects on the proliferation of progenitor cells. This might be mediated by a decrease in vascular endothelial growth factor (VEGF) transcripts in the hippocampus of knockout animals. At the behavioural level, while NOS-III knockout mice displayed better and faster learning in a learned helplessness paradigm, no depression-like behaviours were observed. In conclusion, our results indicated that NOS-III is involved in the proliferation of neuronal progenitor cells, although behavioural analysis does not provide evidence for a pro-depressive effect of reduced neuroneogenesis.