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Synaptic Integration of Adult-Generated Olfactory Bulb Granule Cells: Basal Axodendritic Centrifugal Input Precedes Apical Dendrodendritic Local Circuits

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Synaptic Integration of Adult-Generated Olfactory Bulb Granule Cells: Basal Axodendritic Centrifugal Input Precedes Apical Dendrodendritic Local Circuits Synaptic Integration of Adult-Generated Olfactory Bulb Granule Cells: Basal Axodendritic Centrifugal Input Precedes Apical Dendrodendritic Local Circuits The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Whitman, M. C., and C. A. Greer. 2007. “Synaptic Integration of Adult-Generated Olfactory Bulb Granule Cells: Basal Axodendritic Centrifugal Input Precedes Apical Dendrodendritic Local Circuits.” Journal of Neuroscience 27 (37) (September 12): 9951–9961. doi:10.1523/jneurosci.1633-07.2007. Published Version 10.1523/JNEUROSCI.1633-07.2007 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37156019 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA The Journal of Neuroscience, September 12, 2007 • 27(37):9951–9961 • 9951 Development/Plasticity/Repair Synaptic Integration of Adult-Generated Olfactory Bulb Granule Cells: Basal Axodendritic Centrifugal Input Precedes Apical Dendrodendritic Local Circuits Mary C. Whitman1 and Charles A. Greer1,2 Departments of 1Neurobiology and 1Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520-8082 The adult mammalian olfactory bulb (OB) receives a continuing influx of new interneurons. Neuroblasts from the subventricular zone (SVZ) migrate into the OB and differentiate into granule cells and periglomerular cells that are presumed to integrate into the synaptic circuits of the OB. We have used retroviral infection into the SVZ of mice to label adult-generated granule cells and follow their differen- tiation and integration into OB circuitry. Using synaptic markers and electron microscopy, we show new granule cells integrating into the reciprocal circuitry of the external plexiform layer (EPL), beginning at 21 d postinfection (dpi). We further show that synapses are formed earlier, beginning at 10 dpi, on the somata and basal dendrites of new cells in the granule cell layer (GCL), before dendritic elaboration in the EPL. In the EPL, elaborate dendritic arbors with spines are first evident at 14 dpi. The density of spines increases from 14 to 28 dpi, and then decreases by 56 dpi. Despite the initial appearance of dendritic spines at 14 dpi in the EPL, no expression of presynaptic or postsynaptic markers is seen until 21 dpi. These data suggest that adult-generated granule cells are first innervated by centrifugal or mitral/tufted cell axon collaterals in the GCL and that these inputs may contribute to their differentiation, maturation, and synaptic integration into the dendrodendritic local circuits found in the EPL. Key words: neurogenesis; synaptogenesis; dendrite; spine; cholinergic; rostral migratory stream Introduction dendritic arbors without spines. Stage 5 cells (days 15–30) have Ongoing neurogenesis contributes new interneurons to the adult mature morphologies with spiny dendrites. Between 15 and 45 d olfactory bulb (OB) and dentate gyrus (for review, see Lledo et al., after generation, 50% of adult-generated granule cells die (Pe- 2006). In the dentate, granule cells generated in the subgranular treanu and Alvarez-Buylla, 2002), perhaps reflecting their failure zone migrate into the overlying granule cell layer and integrate to integrate into synaptic circuits. into existing synaptic circuits (Ming and Song, 2005; Ge et al., The membrane properties of adult-generated cells with ma- 2006; Zhao et al., 2006). New OB cells are generated in the sub- ture morphology are indistinguishable from those of older cells ventricular zone (SVZ) and migrate several millimeters through (Carleton et al., 2003). Odor stimulation increases survival in the rostral migratory stream (RMS) to the OB where they differ- newborn granule cells (Rochefort et al., 2002; Magavi et al., 2005; entiate into granule cells and periglomerular (PG) cells (Whit- Alonso et al., 2006), whereas deprivation appears to decrease man and Greer, 2007). differentiation and survival (Saghatelyan et al., 2005; Yamaguchi Differentiation and maturation of adult-generated OB gran- and Mori, 2005). ule cells occurs in five stages (Petreanu and Alvarez-Buylla, 2002). Evidence for the formation of synapses by adult-generated OB Cells in stages 1 and 2 (days 2–7 postretroviral infection) are cells has been elusive. Carlen et al. (2002) reported transsynaptic migratory, with a prominent leading process and a small trailing transport of pseudorabies virus from mitral cells into adult- process. Stage 3 cells (days 9–13) reach the granule cell layer generated PG cells. Similarly, PG cells beginning at 24 d appear (GCL) and have a simple dendrite extending toward, but not apposed to synapsin ϩ puncta and exhibit diffuse colocalization past, the mitral cell layer. Stage 4 cells (days 11–22) have extensive of synaptic vesicle protein 2 (Belluzzi et al., 2003). Synaptophysin puncta appear proximal to the somata and basal dendrite of Received April 11, 2007; revised July 27, 2007; accepted July 30, 2007. adult-generated granule cells, but evidence for their integration This work was supported by National Institutes of Health Grants DC00210, DC006972, DC006291, and AG028054 into functional external plexiform layer (EPL) synaptic circuits (C.A.G.). M.C.W. was supported by Yale Medical Scientist Training Program Grant GM07205. We thank Dolores remains inconclusive (Magavi et al., 2005). In addition to their MontoyaandChristineKaliszewskifortechnicalassistance,Drs.DiegoRodriguezGil,FumiakiImamura,LorenaRela, and Helen Treloar for critical reading of this manuscript, and all members of the laboratory for ongoing discussions dendrodendritic circuits in the EPL, granule cells also receive and advice. We also thank Drs. Pierre-Marie Lledo and Mariana Alonso of the Pasteur Institute (Paris, France) for centrifugal synapses onto their somata and basal dendrites in the encouragement and advice. GCL (Shepherd et al., 2004), but these have not been addressed in CorrespondenceshouldbeaddressedtoDr.CharlesA.Greer,DepartmentofNeurosurgery,YaleUniversitySchool the context of adult neurogenesis. of Medicine, P.O. Box 208082, New Haven, CT 06520-8082. E-mail: [email protected]. DOI:10.1523/JNEUROSCI.1633-07.2007 We present evidence that adult-generated granule cells are Copyright © 2007 Society for Neuroscience 0270-6474/07/279951-11$15.00/0 fully integrated into OB synaptic circuits. Significantly, we show 9952 • J. Neurosci., September 12, 2007 • 27(37):9951–9961 Whitman and Greer • Synaptogenesis in the Adult Olfactory Bulb ␣ that new granule cells first receive synapses on their cell bodies Synaptic Systems); and rabbit anti-GABAA 1 (1:100; Alomone Labs, and basal dendrites, considerably before synapse formation on Jerusalem, Israel). their apical dendrites. We also demonstrate that granule cell den- Secondary antibodies and concentrations dritic spines can form bidirectional dendrodendritic synapses, Secondary antibodies and concentrations used were as follows: donkey beginning at 21 d postinfection (dpi) and that the stabilization of anti-mouse-Alexa 488 (1:1000; Invitrogen); donkey anti-rabbit-Alexa the EPL circuits parallels a transient hypertrophy of spines. The 488 (1:1000; Invitrogen); donkey anti-mouse-Alexa 555 (1:1000; Invitro- precocious formation of synapses onto the basal compartments gen); donkey anti-rabbit-Alexa 555 (1:1000; Invitrogen); donkey anti- of the newborn granule cells suggests a more important role of rabbit-biotin (1:1000; Jackson ImmunoResearch, West Grove, PA); and centrifugal and mitral cell axon collaterals in the differentiation horse anti-goat-biotin (1:1000; Vector). and stabilization of adult-generated cells than hypothesized Image acquisition and analysis previously. Images were acquired with a Leica (Wetzlar, Germany) confocal micro- scope, using 40ϫ or 63ϫ oil-immersion objectives, and up to 3.24ϫ digital zoom. Z-stacks were taken through the area of interest, with 0.12– Materials and Methods ␮ Animals 0.5 m steps between images. Unless otherwise indicated, images dis- For retroviral injection, ϳ1 ␮l of concentrated retrovirus (10 8 cfu/ml) played are the maximum projections, generated with Leica confocal soft- encoding tau green fluorescent protein (tauGFP; a kind gift from Drs. A. ware. Levels were adjusted in Adobe (San Jose, CA) Photoshop, but the Chesler and S. Firestein, Columbia University, New York, NY) was in- images were otherwise unaltered. jected in 6- to 9-week-old male C57BL/6 mice (Charles River Laborato- Spine density was measured on distal dendritic segments using maxi- ries, Wilmington, MA) at the following coordinates (in millimeters) rel- mum projections of high magnification images. Dendrite length was ative to bregma: anterior, 0.0; lateral, Ϯ1.0; depth, 2.2. The retrovirus, measured by drawing a line along the dendrite and measuring the length derived from Moloney murine leukemia virus, infects only dividing cells of the line, using MetaMorph software. The number of spines along that and is replication incompetent (Chesler et al., 2007). After recovery, length was manually counted, and divided by the length to get a measure animals were housed singly with a 12 h light/dark cycle and access to food of density. For each time point, between 37 and 60 individual dendritic and water ad libitum. All animal care and use was approved by the Yale lengths were measured, from a minimum
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