| Summary: | Neuropeptide Y (NPY) is widely expressed in the central and peripheral nervous systems and is proliferative for a range of cells types in vitro. NPY plays a key role in regulating adult hippocampal neurogenesis in vivo under both basal and pathological conditions, although the underlying mechanisms are largely unknown. We have investigated the role of nitric oxide (NO) on the neurogenic effects of NPY. Using postnatal rat hippocampal cultures, we show that the proliferative effect of NPY on nestin-positive precursor cells is NO-dependent. As well as the involvement of neuronal nitric oxide synthase, the proliferative effect is mediated via a NO/cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG) and extracellular signal-regulated kinase (ERK) 1/2 signalling pathway. We show that NPY-mediated intracellular NO signalling results in an increase in neuroproliferation. By contrast, extracellular NO had an opposite, inhibitory effect, on proliferation. The importance of the NO-cGMP-PKG signalling pathway in ERK 1/2 activation was confirmed using western blotting. This work unites two significant modulators of hippocampal neurogenesis within a common signalling framework and provides a mechanism for the independent extra- and intracellular regulation of postnatal neural precursors by NO.
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