Neuropeptide y modulates hippocampal neurogenesis

Abstract

NPY and its predominant receptors Y1, Y2 and Y5 are abundantly expressed in the hippocampus and dentate and we hypothesised that some of NPY’s activity might be through its effects on neurogenesis, and sought to determine if NPY was neuroproliferative for cells of the hippocampus. We have demonstrated that NPY is proliferative for nestin-positive cells with stem/progenitor cell characteristics and for class III β-tubulin-positive neuroblasts via specific activation of Y1 receptors.  Using dentate and hippocampus-derived cultures (containing attached cells of the alveus and periventricular neurogenic margins) we have demonstrated that nestin-positive cells express Lewis-X, generate neurospheres and give rise to mature astrocytes and neurons on removal of the NPY growth stimulus.  NPY is only proliferative for neuroblasts within dentate-derived cultures.  Young adult Y1 receptor knockout mice and adult NPY knockout mice both display reduced subgranular zone cell proliferation in comparison to respective littermate controls, while the number of new neurons is also reduced in Y1-/- animals.  NPY knockout mice have a lower number of proliferating cells following chemoconvulsant seizures in comparison to wild type animals matched for both dose of chemoconvulsant and severity of seizures.  GABA and NPY are often co-expressed in interneurons, and GABAA receptor activation abolishes the proliferative effect of NPY, indicating that the balance in GABA/NPY tone in the hippocampus could regulate cell proliferation and differentiation. This work suggests that NPY modulates neurogenesis through development and into adulthood, and raises the intriguing possibility that much of NPY’s involvement in processes of learning or in depression is based upon its control of hippocampal neurogenesis.</p