NPY promotes chemokinesis and neurogenesis in the rat subventricular zone

Abstract

1These authors contributed equally to the work.Abbreviations used: BrdU, bromodeoxyuridine; EGF, epidermal growth factor; NPY, neuropeptide Y; NSC, neural stem cell; SFM, serum-free medium; SVZ, subventricular. AbstractThe subventricular zone (SVZ) is a major reservoir for stem cells in the adult mammalian brain. Neural stem cells supply the olfactory bulb with new interneurons and provide cells that migrate towards lesioned brain areas. Neuropeptide Y (NPY), one of the most abundant neuropeptides in the brain, was previously shown to induce neuroproliferation on mice SVZ cells. In the present study, performed in rats, we demonstrate the endogenous synthesis of NPY by cells in the SVZ that suggests that NPY could act as an autocrine/paracrine factor within the SVZ area. We observed that NPY promotes SVZ cell proliferation as previously reported in mice, but does not affect self-renewal of SVZ stem cells. Additionally, this study provides the first direct evidence of a chemokinetic activity of NPY on SVZ cells. Using pharmacological approaches, we demonstrate that both the mitogenic and chemokinetic properties of NPY involve Y1 receptor-mediated activation of the ERK1/2 MAP kinase pathway. Altogether, our data establish that NPY through Y1 receptors activation controls chemokinetic activity and, as for mice, is a major neuroproliferative regulator of rat SVZ cells.

Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease

“…It has been previously reported that NPY promotes self-renewal of neural progenitor cells in the subgranular zone of the dentate gyrus (61); however, it only induces neuronal differentiation in the subventricular zone where it fails to promote self-renewal (62,63). In fact, previous reports have shown that the increase in proliferation in the subgranular zone is through the NPY R1 receptor via the ERK pathway (58,64,65); a receptor that we show in this report is activated by our recombinant NPY-apoB consistent with these previous findings.…”

Neurotransmitter-mediated control of neurogenesis in the adult vertebrate brain

“…In the hippocampus, NPY is expressed by the GABAergic interneurons that are situated in the hilus and in the DG (Köhler et al, 1986;Freund and Buzsáki, 1996). In vivo and in vitro studies show that NPY has a pro-proliferative effect in both the SVZ and the SGZ (Howell et al, 2005;Agasse et al, 2008;Decressac et al, 2009;Thiriet et al, 2011).…”

“…In the hippocampus, NPY is expressed by the GABAergic interneurons that are situated in the hilus and in the DG (Köhler et al, 1986;Freund and Buzsáki, 1996). In vivo and in vitro studies show that NPY has a pro-proliferative effect in both the SVZ and the SGZ (Howell et al, 2005;Agasse et al, 2008;Decressac et al, 2009;Thiriet et al, 2011).Studies using knockout mice and receptor-specific modulators found that the Y1 receptor is essential for the NPY-mediated effect on progenitor proliferation (Hansel et al, 2001;Howell et al, 2005;Agasse et al, 2008;Decressac et al, 2009). A recent study points towards an epistatic relationship between NPY and NO signaling REVIEW Development 140 (12) (Cheung et al, 2012).…”

Towards improved receptor targeting: anterograde transport, internalization and postendocytic trafficking of neuropeptide Y receptors

“…The most prominent role of this Y 1 receptor subtype is the induction of food intake and the re gulation of energy homeostasis in synergy with Y 5 (Nguyen et al , 2012 ). Moreover, the Y 1 receptor modulates vasoconstriction (Hodges et al , 2009 ) and conveys neuroregenerative effects in vitro and in vivo (Howell et al , 2005 ;Thiriet et al , 2011 ) , as well as antidepressant and anxiolytic effects in rodents (Wahlestedt et al , 1993 ;Verma et al , 2012 ). The hY 1 is overexpressed in more than 84% of primary human breast (Reubi et al , 2001 ) and Ewing sarcoma tumors , representing a promising diagnostic and therapeutic target for these types of cancer.…”

“…Like all GPCR, the Y receptors consist of seven transmembrane-spanning helices, three intra-and extracellular loops (ECLs), and an external amino(N-)-and an internal carboxy(C-)-terminus. Their activation leads to the inhibition of the adenylate cyclase, the modulation of potassium and calcium channels and, in some cell types, to the phosphorylation of p44/42 mitogen-activated protein kinases (MAPKs) and their downstream effectors (Howell et al , 2005 ;Lu et al , 2010 ;Thiriet et al , 2011 ;Shimada et al , 2012 ). Five Y receptors have been cloned from mammals, namely Y 1 , Y 2 , Y 4 , Y 5 and y 6 .…”