Cellular targets for neuropeptide Y-mediated control of adult neurogenesis

Abstract

Neuropeptides are emerging as key regulators of stem cell niche activities in health and disease, both inside and outside the central nervous system (CNS). Among them, neuropeptide Y (NPY), one of the most abundant neuropeptides both in the nervous system and in non-neural districts, has become the focus of much attention for its involvement in a wide range of physiological and pathological conditions, including the modulation of different stem cell activities. In particular, a pro-neurogenic role of NPY has been evidenced in the neurogenic niche, where a direct effect on neural progenitors has been demonstrated, while different cellular types, including astrocytes, microglia and endothelial cells, also appear to be responsive to the peptide. The marked modulation of the NPY system during several pathological conditions that affect neurogenesis, including stress, seizures and neurodegeneration, further highlights the relevance of this peptide in the regulation of adult neurogenesis. In view of the considerable interest in understanding the mechanisms controlling neural cell fate, this review aims to summarize and discuss current data on NPY signaling in the different cellular components of the neurogenic niche in order to elucidate the complexity of the mechanisms underlying the modulatory properties of this peptide.

Keywords: astrocyte; endothelium; microglia; neural stem cells; neurogenesis; neurogenic niche; neuropeptide Y.

Figure 1

Schematic drawing indicating the main effects exerted by neuropeptide Y (NPY) on the different components of the neurogenic niche. NPY, released by different sources in both physiological and pathological conditions, directly targets selected neural stem cell (NSC) subtypes (namely nestin- and doublecortin [DCX]-positive cells), inducing proliferation, differentiation, migration and functional integration of newly-born neurons. NPY also modulates microglia functions: through the interaction with the Y1R, it inhibits microglial activation and interleukin (IL)-1beta release. The influence of NPY-microglia interactions in the modulation of neurogenesis (dotted black arrow) may be hypothesized. In addition, NPY stimulates astrocyte proliferation mainly via the Y1 receptors (Y1R). NPY also acts on the endothelium through the Y2 receptors (Y2R), in cooperation with the Y5 receptors (Y5R): consequently a direct effect on the endothelial component of the neurogenic niche could be hypothesized (dotted yellow arrow), resulting in increased angiogenesis and possible modulation of endogenous neurogenesis (dotted black arrow).

Figure 2

Neuropeptide Y (NPY) mediates cell-cell interactions within the neurogenic niche. NPY may be involved as key player of the complex communication process among the different components of the niche (neural stem cell [NSCs], microglia, astrocytes and endothelium) (black arrows).