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Turning Astrocytes from the Rostral Migratory Stream Into Neurons: a Role for the Olfactory Sensory Organ

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Turning Astrocytes from the Rostral Migratory Stream Into Neurons: a Role for the Olfactory Sensory Organ The Journal of Neuroscience, October 22, 2008 • 28(43):11089–11102 • 11089 Development/Plasticity/Repair Turning Astrocytes from the Rostral Migratory Stream into Neurons: A Role for the Olfactory Sensory Organ Mariana Alonso,1 Inmaculada Ortega-Pe´rez,1 Matthew S. Grubb,1 Jean-Pierre Bourgeois,1 Pierre Charneau,2 and Pierre-Marie Lledo1 1Laboratory for Perception and Memory, Centre National de la Recherche Scientifique, Unite´ de Recherche Associe´e 2182, and 2Laboratory of Molecular Virology and Vectorology, Institut Pasteur, 75724 Paris Cedex 15, France Neurogenesis persists within a few restricted areas of the adult mammalian brain, giving rise to neurons that functionally integrate into preexisting circuits. One of these areas, the subventricular zone (SVZ), was believed, until recently, to be the unique source providing the adult olfactory bulb (OB) with newborn neurons. Because of the fact that neuroblasts derived in the SVZ migrate through the rostral migratory stream (RMS) en route to the OB, the existence of candidate neural stem cells within the RMS was long overlooked. Here, we confirm and considerably extend recent evidence for the existence of adult neural stem cells within the RMS, and go on to investigate their proliferative regulation. Specifically targeting RMS-astrocytes with lentiviral vectors encoding GFP, we demonstrate that glial cells in the RMSdifferentiateintobothOBgranuleandperiglomerularinterneurons.Inaddition,ultrastructuralanalysisunambiguouslyrevealsthe astrocytic nature of stem cells in the adult RMS, and patch-clamp recordings demonstrate the functional integration of RMS-derived interneurons into OB circuitry. Proliferative regulation was investigated via two contrasting manipulations: exposure to an odor- enrichedenvironmentthatenhancescandidatestemcellproliferationinboththeRMSandSVZ,andchemicallesionofthemainolfactory epithelium that increases cell proliferation in the RMS only. New neurons in the adult OB can therefore arise from different neurogenic areas that can be separately regulated. Key words: adult neurogenesis; astrocytes; interneurons; GABA; neural stem cells; stem cells Introduction whereas astrocytes delineating the glial tubes of the RMS remain New neurons continue to be integrated into the olfactory bulb quiescent (Menezes et al., 1995; Rousselot et al., 1995; Bru¨stle et (OB) circuit of adult mammals, including humans (for review, al., 1998; but see Peretto et al., 2005; Merkle et al., 2007). see Lledo et al., 2006; Curtis et al., 2007). Previous investigations Radial glial cells serve as progenitors for many neurons and have shown that astrocytes function as progenitors of the new- glial cells soon after birth and they also give rise to adult neural born neurons generated in the adult subventricular zone (SVZ) stem cells (Merkle et al., 2004). During postnatal developmental (Alvarez-Buylla et al., 2001). From there, neuroblasts migrate modification of the SVZ, in its rostral extension, radial glia dif- along a well defined pathway, the rostral migratory stream ferentiate into astrocytes packed to form the glial tubes in the (RMS), en route to the OB where they differentiate into local mature RMS (for review, see Bonfanti and Peretto, 2007). After interneurons (Luskin, 1993; Lois and Alvarez-Buylla, 1994). Un- the postnatal collapse of the olfactory ventricle, only the middle/ like other neuronal precursor populations generated during de- posterior part of the SVZ remains in contact with the lateral velopment, neuroblasts in the RMS are still mitotically active, ventricles, with the anterior part forming the mature RMS. How- ever, apart from the absence of the ependymal cellular monolayer Received Aug. 5, 2008; revised Sept. 8, 2008; accepted Sept. 11, 2008. in the RMS, the cytoarchitecture of the SVZ and RMS remains This work was supported by the Fe´de´ration pour la Recherche sur le Cerveau, the Agence Nationale de la Recher- substantially similar. In this context, it is tempting to propose che (ANR-05-Neur-028-01), the Groupe Arpe`ge, Ecole des Neurosciences de Paris, and the Fondation Institut de that astrocytes derived from radial glia, and possessing stem cell France. Our laboratory is a member of the Network of European Neuroscience Institutes (Grant LSHM-CT-2005- properties, might be also present throughout the entire RMS up 019063). M.A. was supported by a grant from the Re´gion Ile-de-France (Neuropoˆle 07-006); I.O.-P. by a grant from the Re´gion Aquitaine; and M.S.G. by a Marie-Curie IntraEuropean Fellowship. We thank A. de Chevigny for his help to the core of the OB. This hypothesis is supported by data show- in preliminary experiments, I. Caille for advice on the mini-osmotic pump implantation technique, the PFID for ing that after anti-mitotic treatment, fast-proliferating cells can technical assistance with confocal microscopy, A.-M. Le Sourd for helping us with electron microscopy experiments, be detected in the RMS (Gritti et al., 2002). Similarly, the tran- G. Gheusi for helping us with olfactory enrichment experiments, P. Souque for his help with Mokola vector stability sient recovery of OB neuronal populations after SVZ irradiation experiments, and S. Mejia Gervacio for helpful comments. Correspondence should be addressed to Pierre-Marie Lledo at the above address. E-mail: [email protected]. (Panagiotakos et al., 2007), also confirms the presence of neural M. S. Grubb’s present address: MRC Centre for Developmental Neurobiology, King’s College London, New Hunt’s precursors downstream from the SVZ. The nature and origin of House, 4th Floor, Guy’s Hospital Campus, London SE1 1UL, UK. these progenitors remained unknown until a recent study de- I. Ortega-Perez’s present address: INSERM Unit 679, Experimental Neurology and Therapeutics, Pitie´-Salpeˆtrie`re scribed GFAP-expressing astrocytes located in the most rostral Hospital, 47 Bd de l’Hoˆpital, 75651 Paris Cedex 13, France. DOI:10.1523/JNEUROSCI.3713-08.2008 part of the SVZ (Merkle et al., 2007). Copyright © 2008 Society for Neuroscience 0270-6474/08/2811089-14$15.00/0 The present work explores the ability of RMS-astrocytes to 11090 • J. Neurosci., October 22, 2008 • 28(43):11089–11102 Alonso et al. • Regulation of Neural Stem Cell Proliferation in the RMS produce functionally integrated neurons Table 1. Detailed information on the primary antibodies used in this study in the mature OB circuit, and investigates Antibody name Manufacturer Working dilution whether this neural production could be Anti-BrdU AbD Serotec 1:200 regulated by the olfactory system. We used Rat monoclonal IgG2a confocal and electron microscopy to re- Anti-GFAP Neomarkers 1:200 veal the glial nature of candidate RMS Mouse monoclonal IgG1 stem cells, whereas lentiviral labeling com- Anti-GFP Invitrogen 1:1000 bined with electrophysiological recordings Rabbit polyclonal deciphered the identity and the functional Anti-MASH1 BD Pharmingen 1:100 properties of their neuronal progeny in the Mouse monoclonal IgG1 OB. Finally, lesion of the main olfactory Anti-NeuN Millipore Bioscience Research Reagents 1:200 epithelium (MOE) and exposure to an Mouse monoclonal IgG1 odor-enriched environment showed that Anti-NG2 Millipore Bioscience Research Reagents 1:100 Rabbit polyclonal stem cell proliferation in this most rostral Anti-OMP Kindly provided by Dr. F. Margolis (Baltimore, MD) 1:2000 neurogenic region can be regulated by the Goat polyclonal olfactory sensory organ, and can some- Anti-PSA-NCAM AbCys 1:200 times be regulated separately from adult Mouse monoclonal IgM neurogenesis in the SVZ. Anti-SOX2 Millipore Bioscience Research Reagents 1:200 Rabbit polyclonal Materials and Methods Anti-S100␤ Swant 1:100 Subjects Rabbit polyclonal Two-month-old C57BL/6 mice were used Anti-O4 Millipore Bioscience Research Reagents 1:200 throughout this study (Janvier). Mice were kept Mouse monoclonal IgM in a temperature- (20 Ϯ 1°C) and light- controlled room. Food and water were available ad libitum. All experimental procedures were Histological analysis performed in accordance with the Society for Neuroscience and Euro- Immunohistochemistry. Mice were deeply anesthetized with sodium pen- pean Union guidelines, and were approved by our institutional animal tobarbital (100 mg/kg; Sanofi) and perfused through the heart with a care and utilization committees. saline solution (0.9% NaCl) containing heparin (5.10 3 U/ml) at 37°C, followed by 4% paraformaldehyde (PFA) in cold phosphate buffer (PB), Ara-C and lentiviral vector injections pH 7.3. Brains were dissected out and postfixed in the same fixative Ara-C infusions. Cystosine-␤-D-arabinofuranoside (Ara-C, 2%; Sigma) overnight at 4°C. Immunohistochemistry was performed on 40 ␮m- in 0.9% saline solution or vehicle alone was infused onto the surface of thick free-floating serial parasagittal sections cut with a vibrating mic- the brain with a mini-osmotic pump (Alzet; model 1007D) (flow rate 0.5 rotome (VT1000S; Leica). For GFAP and PSA-NCAM immunostaining, ␮ ␮ l/hour, 6 d). Mice were anesthetized with 250 l of a mixture of ket- antigen retrieval was performed for 20 min at 65°C in 1 mM EDTA. For amine (Imalgene; 1.5% in PBS) and xylazine (Rompum; Bayer Health SOX2 immunostaining, antigen retrieval was performed for 20 min at Care; 0.025% in PBS), and were mounted in a Kopf stereotaxic apparatus 100°C in 1 mM EDTA, 0.05% Tween. Brain sections were then washed in (Harvard Apparatus). Cannulas were implanted stereotaxically onto the PBS and treated with 0.2% Triton X-100, 4% BSA in PBS for2htoblock surface of the brain at the coordinates: 0 mm anterior to bregma, 1.1 mm nonspecific protein binding sites and to permeabilize membranes. For lateral of midline, and Ϫ0.1 mm from brain surface. BrdU staining, DNA was denatured with 2 N HCl for 30 min at 37°C. Lentiviral vectors and stereotaxic injections. Immediately after the end Incubation with primary antibodies was performed individually (see Ta- of Ara-C infusion, pumps were removed and the mice were stereotaxi- ble 1 for the list of primary antibodies) at 4°C for 2 d [except for anti-GFP cally injected with lentiviral vector particles using the same anesthesia as and anti-SOX2, which were incubated overnight at 4°C and 24 h at room described above.
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