Neuropeptide Y is important for basal and seizure-induced precursor cell proliferation in the hippocampus
Introduction
Neurogenesis, the production of new neurons, is a restricted event in the postnatal and adult mammalian brain (Altman and Das, 1965, Kaplan and Hinds, 1977, Gross, 2000), confined to the subventricular zone (SVZ) around the anterior lateral ventricle and rostral migratory stream to the olfactory bulb (Luskin, 1993, Lois and Alvarez-Buylla, 1994), the subgranular zone (SGZ) of the dentate gyrus (Altman and Das, 1965) and the cornu ammonis of the hippocampus (Rietze et al., 2000). There has been much interest in elucidating the role of adult neurogenesis in the dentate gyrus in the normal brain, where it appears to regulate hippocampal-dependent learning and memory (Shors et al., 2001, van Praag et al., 2002) as well as mood control (D’Sa and Duman, 2002, Santarelli et al., 2003).
Adult neurogenesis in the dentate gyrus may also contribute to the sequelae that follow seizures. Seizures increase neurogenesis in both the SGZ and rostral SVZ (Bengzon et al., 1997, Parent et al., 1997, Parent et al., 2002, Gray and Sundstrom, 1998, Scott et al., 1998) and gliogenesis in the caudal SVZ (cSVZ) (Parent et al., 2006). The mechanisms underlying seizure-induced neurogenesis/gliogenesis are incompletely understood, but clearly involve an increase in precursor cell proliferation. GFAP-expressing astrocytes appear to give rise to transiently amplifying C cells and proliferating neuroblasts (D cells) in the anterior SVZ (Doetsch et al., 1999), while radial glia-like astrocytes give rise to proliferating neuroblasts (D1 cells) either directly (Seri et al., 2001, Seri et al., 2004), or via a weakly nestin-positive amplifying cell population (Encinas et al., 2006), in the SGZ. Seizures increase the proliferation of neuroblasts in the rostral SVZ (Parent et al., 2002) and of both radial glia-like precursor cells (Huttmann et al., 2003) and doublecortin-positive cells in the SGZ of the dentate gyrus (Jessberger et al., 2005).
Dissecting the precise mechanisms underlying the effects of seizures on different precursor cell types has been hindered by the lack of a unique marker for precursor cells in these neurogenic niches. The intermediate filament protein nestin is expressed in precursor cells during development, and in subpopulations of cells in both neurogenic and non-neurogenic regions of the postnatal brain (Wei et al., 2002). In vivo studies have shown that nestin expression can be detected immunohistochemically in stem cells of the cSVZ (Gates et al., 1995, Wei et al., 2002) and in GFAP-positive radial glia-like precursor cells in the dentate SGZ (Seri et al., 2004). Nestin expression is controversial in SGZ neuroblasts (D1 or Type 2 cells), which are the mitotic progeny of GFAP-positive radial glia-like precursor cells. Nestin expression has been inferred in these Type 2 cells by transient GFP expression in nestin reporter transgenic mice (Fukuda et al., 2003, Kronenberg et al., 2003) but has not been confirmed by direct immunohistochemical detection (Seri et al., 2004). However, a recent study using a nuclear-localized reporter of nestin gene expression, has identified a nestin-positive/β-tubulin-negative, transiently amplifying mitotic cell population, that arises from GFAP/nestin-expressing precursors in the SGZ, and which divides to give rise to β-tubulin-expressing immature neurons (Encinas et al., 2006).
Amidated neuropeptides, such as neuropeptide Y (NPY) (Hansel et al., 2001a) and pituitary adenylate cyclase-activating polypeptide (PACAP) are emerging as significant regulators of adult neural stem cells in the olfactory epithelium (Hansel et al., 2001b) and hippocampus (Howell et al., 2003, Howell et al., 2005, Mercer et al., 2004, Ohta et al., 2006). We have previously shown that an inhibitory peptide neurotransmitter, neuropeptide Y (NPY), released by GABAergic interneurons in the dentate gyrus and pyramidal layers of the hippocampus, is a potent proliferative factor acting through its Y1 receptor, for neuroblasts and nestin-positive sphere-forming stem cells in cultures of the whole hippocampus from early postnatal rats (Howell et al., 2003). We have recently shown that the Y1 receptor-mediated proliferative effect on neuroblasts (D1 or Type 2 cells) is confined to those neuroblasts isolated from the DG, but not from the hippocampus or adjacent subependymal regions (Howell et al., 2005). However, the nature and location of the nestin-positive NPY-responsive population remain unknown.
Since NPY is significantly up-regulated in the DG and hippocampus after status epilepticus (Marksteiner et al., 1989) and status epilepticus increases precursor proliferation in the DG leading to neurogenesis, and subventricular areas of the hippocampus leading to gliogenesis, we examined the effect of NPY on region-specific primitive nestin-positive precursor cells and sought to determine if NPY plays a role in seizure-induced precursor cell proliferation.
Section snippets
Animals
Animals were maintained on a 12-h light:dark cycle and provided food and water ad libitum. Rats (Wistar) were obtained from (Harlan; UK). NPY Y1 receptor−/− mice and their wild-type controls were obtained from Herbert Herzog, details of which have been previously published (Howell et al., 2003). Animal experimentation was approved by a University Bio-Ethics Committee and performed under UK Home Office license or NY State Department of Health Guidelines. Experiments were carried out in
Nestin-positive and Class III β-tubulin-positive cells are distinct but variably overlapping populations at 3 days, in whole hippocampal cultures
Whole hippocampus-derived cultures were examined at 3 days in culture. 100% of nestin cells were actively proliferating (Ki67-positive) compared to 80% of β-tubulin cells (Figs. 1A and B). Immunostaining for both nestin and β-tubulin revealed overlapping populations, with 38% ± 7.8% of nestin cells co-labeled for β-tubulin and 52% ± 6.4% of β-tubulin cells stained for nestin (Fig. 1C). Interestingly 86% of β-tubulin/nestin-positive cells had a punctate and largely cytoplasmic staining pattern of
Nestin-positive cells in the dentate gyrus and hippocampus
The rodent dentate gyrus is partly formed in the embryo, when progenitor cells migrate within the hippocampal migratory stream to the developing dentate gyrus around E18 to establish the tertiary germinal matrix in the hilus (Pleasure et al., 2000), which continues to directly generate granule cell neurons until P15–20, by which time it has receded to form the adult neurogenic subgranular zone (SGZ). Recently, a second transient (P0–P14) germinal matrix near the fimbria, called the hippocampal
Acknowledgments
The authors gratefully acknowledge the technical help of Dr. Matt Cuttle with confocal microscopy. This work was funded by the MRC (Grant No. G0300356), the University of Southampton Grant No. D04 and the Wessex Medical Trust Hope to W.P.G.
References (62)
- et al.
LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal
Neuron
(2002) - et al.
Subventricular zone astrocytes are neural stem cells in the adult mammalian brain
Cell
(1999) - et al.
Decreased epileptic susceptibility correlates with neuropeptide Y overexpression in a model of tolerance to excitotoxicity
Brain Res.
(2001) - et al.
Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes
Mol. Cell. Neurosci.
(2003) - et al.
Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat
Brain Res.
(1998) - et al.
Tonic–clonic seizures induce division of neuronal progenitor cells with concomitant changes in expression of neurotrophic factors in the brain of pilocarpine-treated mice
Brain Res. Mol. Brain Res.
(2005) - et al.
Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells
Exp. Neurol.
(2005) - et al.
Expression of the neuropeptide Y Y1 receptor in the CNS of rat and of wild-type and Y1 receptor knock-out mice. Focus on immunohistochemical localization(1)
Neuroscience
(2002) Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone
Neuron
(1993)- et al.
Cystatin C modulates neurodegeneration and neurogenesis following status epilepticus in mouse
Neurobiol. Dis.
(2005)
Pilocarpine-induced status epilepticus increases cell proliferation in the dentate gyrus of adult rats via a 5-HT1A receptor-dependent mechanism
Brain Res.
Kindling-induced neurogenesis in the dentate gyrus of the rat
Neurosci. Lett.
Intrinsic differences distinguish transiently neurogenic progenitors from neural stem cells in the early postnatal brain
Dev. Biol.
Pax6 controls the expression of Lewis X epitope in the embryonic forebrain by regulating alpha 1,3-fucosyltransferase IX expression
J. Biol. Chem.
Nestin-containing cells express glial fibrillary acidic protein in the proliferative regions of central nervous system of postnatal developing and adult mice
Brain Res. Dev. Brain Res.
Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats
J. Comp. Neurol.
Knock-out mice reveal a critical antiepileptic role for neuropeptide Y
J. Neurosci.
Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus
Eur. J. Neurosci.
Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures
Proc. Natl. Acad. Sci. U. S. A.
Antidepressants and neuroplasticity
Bipolar Disord.
Fluoxetine targets early progenitor cells in the adult brain
Proc. Natl. Acad. Sci. U. S. A.
Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y
Nature
Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus
J. Neurosci.
Cell and molecular analysis of the developing and adult mouse subventricular zone of the cerebral hemispheres
J. Comp. Neurol.
Neurogenesis in the adult brain: death of a dogma
Nat. Rev., Neurosci.
Neuropeptide Y functions as a neuroproliferative factor
Nature
Regulation of olfactory neurogenesis by amidated neuropeptides
J. Neurosci. Res.
Neuropeptide Y is neuroproliferative for post-natal hippocampal precursor cells
J. Neurochem.
Neuropeptide Y stimulates neuronal precursor proliferation in the post-natal and adult dentate gyrus
J. Neurochem.
Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis
Eur. J. Neurosci.
Phenotypic and functional heterogeneity of GFAP-expressing cells in vitro: differential expression of LeX/CD15 by GFAP-expressing multipotent neural stem cells and non-neurogenic astrocytes
Glia
Cited by (97)
Different types of Status Epilepticus may lead to similar hippocampal epileptogenesis processes
2023, IBRO Neuroscience ReportsNeurogenesis in the damaged mammalian brain
2020, Patterning and Cell Type Specification in the Developing CNS and PNS: Comprehensive Developmental Neuroscience, Second EditionNeural stem cell niche heterogeneity
2019, Seminars in Cell and Developmental BiologyCitation Excerpt :Decrease in the activity of these interneurons promotes increase in the number of quiescent neural stem cells, while conversely activation of parvalbumin + interneurons inhibits the activation of neural stem cells [152,155]. Interneurons expressing neuropeptide Y have been implicated in the control of adult neurogenesis via promoting neural stem cell proliferation [157–159]. Moreover, interneurons expressing vasoactive intestinal peptide (VIP) have been shown to mediate neurogenesis via VIP receptors on neural stem cells [160].
Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies
2018, Pharmacological Reports
- 1
Current address: Division of Neuroscience and Psychological Medicine, Imperial College, London.