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Open Access 01-07-2015 | Original Article

Pre-existing astrocytes form functional perisynaptic processes on neurons generated in the adult hippocampus

Authors: Marine Krzisch, Silvio G. Temprana, Lucas A. Mongiat, Jan Armida, Valentin Schmutz, Mari A. Virtanen, Jacqueline Kocher-Braissant, Rudolf Kraftsik, Laszlo Vutskits, Karl-Klaus Conzelmann, Matteo Bergami, Fred H. Gage, Alejandro F. Schinder, Nicolas Toni

Published in: Brain Structure and Function | Issue 4/2015

Abstract

The adult dentate gyrus produces new neurons that morphologically and functionally integrate into the hippocampal network. In the adult brain, most excitatory synapses are ensheathed by astrocytic perisynaptic processes that regulate synaptic structure and function. However, these processes are formed during embryonic or early postnatal development and it is unknown whether astrocytes can also ensheathe synapses of neurons born during adulthood and, if so, whether they play a role in their synaptic transmission. Here, we used a combination of serial-section immuno-electron microscopy, confocal microscopy, and electrophysiology to examine the formation of perisynaptic processes on adult-born neurons. We found that the afferent and efferent synapses of newborn neurons are ensheathed by astrocytic processes, irrespective of the age of the neurons or the size of their synapses. The quantification of gliogenesis and the distribution of astrocytic processes on synapses formed by adult-born neurons suggest that the majority of these processes are recruited from pre-existing astrocytes. Furthermore, the inhibition of astrocytic glutamate re-uptake significantly reduced postsynaptic currents and increased paired-pulse facilitation in adult-born neurons, suggesting that perisynaptic processes modulate synaptic transmission on these cells. Finally, some processes were found intercalated between newly formed dendritic spines and potential presynaptic partners, suggesting that they may also play a structural role in the connectivity of new spines. Together, these results indicate that pre-existing astrocytes remodel their processes to ensheathe synapses of adult-born neurons and participate to the functional and structural integration of these cells into the hippocampal network.

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Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ, Barres BA (2012) Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486(7403):410–414. doi:10.1038/nature11059 PubMedCentralPubMed

Alonso M, Lepousez G, Sebastien W, Bardy C, Gabellec MM, Torquet N, Lledo PM (2012) Activation of adult-born neurons facilitates learning and memory. Nat Neurosci 15(6):897–904. doi:10.1038/nn.3108 PubMedCrossRef

Altman J (1962) Are new neurons formed in the brains of adult mammals? Science 135(3509):1127–1128PubMedCrossRef

Bergami M, Berninger B (2012) A fight for survival: the challenges faced by a newborn neuron integrating in the adult hippocampus. Dev Neurobiol 72(7):1016–1031. doi:10.1002/dneu.22025 PubMedCrossRef

Bergami M, Santi S, Formaggio E, Cagnoli C, Verderio C, Blum R, Berninger B, Matteoli M, Canossa M (2008) Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes. J Cell Biol 183(2):213–221. doi:10.1083/jcb.200806137 PubMedCentralPubMedCrossRef

Bergles DE, Jahr CE (1998) Glial contribution to glutamate uptake at Schaffer collateral-commissural synapses in the hippocampus. J Neurosci 18(19):7709–7716PubMed

Bruel-Jungerman E, Davis S, Rampon C, Laroche S (2006) Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J Neurosci 26(22):5888–5893. doi:10.1523/JNEUROSCI.0782-06.2006 PubMedCrossRef

Catalani A, Sabbatini M, Consoli C, Cinque C, Tomassoni D, Azmitia E, Angelucci L, Amenta F (2002) Glial fibrillary acidic protein immunoreactive astrocytes in developing rat hippocampus. Mech Ageing Dev 123(5):481–490PubMedCrossRef

Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120(3):421–433. doi:10.1016/j.cell.2004.12.020 PubMedCrossRef

Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ (2009) A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325(5937):210–213. doi:10.1126/science.1173215 PubMedCentralPubMedCrossRef

Colon-Ramos DA, Margeta MA, Shen K (2007) Glia promote local synaptogenesis through UNC-6 (netrin) signaling in C. elegans. Science 318(5847):103–106. doi:10.1126/science.1143762 PubMedCentralPubMedCrossRef

Deshpande A, Bergami M, Ghanem A, Conzelmann KK, Lepier A, Gotz M, Berninger B (2013) Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb. Proc Natl Acad Sci USA 110(12):E1152–E1161. doi:10.1073/pnas.1218991110 PubMedCentralPubMedCrossRef

Dietrich D, Beck H, Kral T, Clusmann H, Elger CE, Schramm J (1997) Metabotropic glutamate receptors modulate synaptic transmission in the perforant path: pharmacology and localization of two distinct receptors. Brain Res 767(2):220–227PubMedCrossRef

Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4(11):1313–1317. doi:10.1038/3305 PubMedCrossRef

Faissner A, Pyka M, Geissler M, Sobik T, Frischknecht R, Gundelfinger ED, Seidenbecher C (2010) Contributions of astrocytes to synapse formation and maturation—potential functions of the perisynaptic extracellular matrix. Brain Res Rev 63(1–2):26–38. doi:10.1016/j.brainresrev.2010.01.001 PubMedCrossRef

Finke S, Mueller-Waldeck R, Conzelmann KK (2003) Rabies virus matrix protein regulates the balance of virus transcription and replication. J Gen Virol 84(Pt 6):1613–1621PubMedCrossRef

Ge S, Yang CH, Hsu KS, Ming GL, Song H (2007) A critical period for enhanced synaptic plasticity in newly generated neurons of the adult brain. Neuron 54(4):559–566. doi:10.1016/j.neuron.2007.05.002 PubMedCentralPubMedCrossRef

Ge WP, Miyawaki A, Gage FH, Jan YN, Jan LY (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484(7394):376–380. doi:10.1038/nature10959 PubMedCentralPubMedCrossRef

Genoud C, Quairiaux C, Steiner P, Hirling H, Welker E, Knott GW (2006) Plasticity of astrocytic coverage and glutamate transporter expression in adult mouse cortex. PLoS Biol 4(11):e343. doi:10.1371/journal.pbio.0040343 PubMedCentralPubMedCrossRef

Gu Y, Arruda-Carvalho M, Wang J, Janoschka SR, Josselyn SA, Frankland PW, Ge S (2012) Optical controlling reveals time-dependent roles for adult-born dentate granule cells. Nat Neurosci 15(12):1700–1706. doi:10.1038/nn.3260 PubMedCentralPubMedCrossRef

Haber M, Zhou L, Murai KK (2006) Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses. J Neurosci 26(35):8881–8891. doi:10.1523/JNEUROSCI.1302-06.2006 PubMedCrossRef

Hagemann TL, Paylor R, Messing A (2013) Deficits in adult neurogenesis, contextual fear conditioning, and spatial learning in a Gfap mutant mouse model of Alexander disease. J Neurosci 33(47):18698–18706. doi:10.1523/JNEUROSCI.3693-13.2013 PubMedCentralPubMedCrossRef

Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, Xu Q, Oberheim NA, Bekar L, Betstadt S, Silva AJ, Takano T, Goldman SA, Nedergaard M (2013) Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12(3):342–353. doi:10.1016/j.stem.2012.12.015 PubMedCentralPubMedCrossRef

Hirrlinger J, Hulsmann S, Kirchhoff F (2004) Astroglial processes show spontaneous motility at active synaptic terminals in situ. Eur J Neurosci 20(8):2235–2239. doi:10.1111/j.1460-9568.2004.03689.xEJN3689 PubMedCrossRef

Huang YH, Bergles DE (2004) Glutamate transporters bring competition to the synapse. Curr Opin Neurobiol 14(3):346–352. doi:10.1016/j.conb.2004.05.007 PubMedCrossRef

Jessberger S, Zhao C, Toni N, Clemenson GD Jr, Li Y, Gage FH (2007) Seizure-associated, aberrant neurogenesis in adult rats characterized with retrovirus-mediated cell labeling. J Neurosci 27(35):9400–9407. doi:10.1523/JNEUROSCI.2002-07.2007 PubMedCrossRef

Kempermann G, Kuhn HG, Gage FH (1997a) Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proc Natl Acad Sci USA 94(19):10409–10414PubMedCentralPubMedCrossRef

Kempermann G, Kuhn HG, Gage FH (1997b) More hippocampal neurons in adult mice living in an enriched environment. Nature 386(6624):493–495. doi:10.1038/386493a0 PubMedCrossRef

Krzisch M, Sultan S, Sandell J, Demeter K, Vutskits L, Toni N (2013) Propofol anesthesia impairs the maturation and survival of adult-born hippocampal neurons. Anesthesiology 118(3):602–610. doi:10.1097/ALN.0b013e3182815948 PubMedCrossRef

Laplagne DA, Esposito MS, Piatti VC, Morgenstern NA, Zhao C, van Praag H, Gage FH, Schinder AF (2006) Functional convergence of neurons generated in the developing and adult hippocampus. PLoS Biol 4(12):e409. doi:10.1371/journal.pbio.0040409 PubMedCentralPubMedCrossRef

Macek TA, Winder DG, Gereau RWt, Ladd CO, Conn PJ (1996) Differential involvement of group II and group III mGluRs as autoreceptors at lateral and medial perforant path synapses. J Neurophysiol 76(6):3798–3806PubMed

Maki R, Robinson MB, Dichter MA (1994) The glutamate uptake inhibitor l-trans-pyrrolidine-2,4-dicarboxylate depresses excitatory synaptic transmission via a presynaptic mechanism in cultured hippocampal neurons. J Neurosci 14(11 Pt 1):6754–6762PubMed

Marin-Burgin A, Mongiat LA, Pardi MB, Schinder AF (2012) Unique processing during a period of high excitation/inhibition balance in adult-born neurons. Science 335(6073):1238–1242. doi:10.1126/science.1214956 PubMedCentralPubMedCrossRef

Mauch DH, Nagler K, Schumacher S, Goritz C, Muller EC, Otto A, Pfrieger FW (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294(5545):1354–1357. doi:10.1126/science.294.5545.1354 PubMedCrossRef

Mishchenko Y, Hu T, Spacek J, Mendenhall J, Harris KM, Chklovskii DB (2010) Ultrastructural analysis of hippocampal neuropil from the connectomics perspective. Neuron 67(6):1009–1020. doi:10.1016/j.neuron.2010.08.014 PubMedCentralPubMedCrossRef

Nishida H, Okabe S (2007) Direct astrocytic contacts regulate local maturation of dendritic spines. J Neurosci 27(2):331–340. doi:10.1523/JNEUROSCI.4466-06.2007 PubMedCrossRef

Nixdorf-Bergweiler BE, Albrecht D, Heinemann U (1994) Developmental changes in the number, size, and orientation of GFAP-positive cells in the CA1 region of rat hippocampus. Glia 12(3):180–195. doi:10.1002/glia.440120304 PubMedCrossRef

Nolte C, Matyash M, Pivneva T, Schipke CG, Ohlemeyer C, Hanisch UK, Kirchhoff F, Kettenmann H (2001) GFAP promoter-controlled EGFP-expressing transgenic mice: a tool to visualize astrocytes and astrogliosis in living brain tissue. Glia 33(1):72–86. doi:10.1002/1098-1136(20010101)33:1<72::AID-GLIA1007>3.0.CO;2-A

Oliet SH, Piet R, Poulain DA (2001) Control of glutamate clearance and synaptic efficacy by glial coverage of neurons. Science 292(5518):923–926. doi:10.1126/science.1059162 PubMedCrossRef

Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L, Poulain DA, Oliet SH (2006) Glia-derived d-serine controls NMDA receptor activity and synaptic memory. Cell 125(4):775–784. doi:10.1016/j.cell.2006.02.051 PubMedCrossRef

Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG (2005) Astrocytic purinergic signaling coordinates synaptic networks. Science 310(5745):113–116. doi:10.1126/science.1116916 PubMedCrossRef

Pfrieger FW, Barres BA (1997) Synaptic efficacy enhanced by glial cells in vitro. Science 277(5332):1684–1687PubMedCrossRef

Platel JC, Dave KA, Gordon V, Lacar B, Rubio ME, Bordey A (2010) NMDA receptors activated by subventricular zone astrocytic glutamate are critical for neuroblast survival prior to entering a synaptic network. Neuron 65(6):859–872. doi:10.1016/j.neuron.2010.03.009 PubMedCentralPubMedCrossRef

Portera-Cailliau C, Pan DT, Yuste R (2003) Activity-regulated dynamic behavior of early dendritic protrusions: evidence for different types of dendritic filopodia. J Neurosci 23(18):7129–7142PubMed

Reye P, Sullivan R, Scott H, Pow DV (2002) Distribution of two splice variants of the glutamate transporter GLT-1 in rat brain and pituitary. Glia 38(3):246–255. doi:10.1002/glia.10059 PubMedCrossRef

Rollenhagen A, Satzler K, Rodriguez EP, Jonas P, Frotscher M, Lubke JH (2007) Structural determinants of transmission at large hippocampal mossy fiber synapses. J Neurosci 27(39):10434–10444. doi:10.1523/JNEUROSCI.1946-07.2007 PubMedCrossRef

Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16(3):675–686PubMedCrossRef

Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R (2011) Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472(7344):466–470. doi:10.1038/nature09817 PubMedCentralPubMedCrossRef

Schmidt-Hieber C, Jonas P, Bischofberger J (2004) Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature 429(6988):184–187. doi:10.1038/nature02553 PubMedCrossRef

Spacek J (1985) Three-dimensional analysis of dendritic spines. III. Glial sheath. Anat Embryol (Berl) 171(2):245–252CrossRef

Stone SS, Teixeira CM, Devito LM, Zaslavsky K, Josselyn SA, Lozano AM, Frankland PW (2011) Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J Neurosci 31(38):13469–13484. doi:10.1523/JNEUROSCI.3100-11.2011 PubMedCrossRef

Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276(5319):1699–1702PubMedCrossRef

Tashiro A, Sandler VM, Toni N, Zhao C, Gage FH (2006) NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 442(7105):929–933. doi:10.1038/nature05028 PubMedCrossRef

Toni N, Sultan S (2011) Synapse formation on adult-born hippocampal neurons. Eur J Neurosci 33(6):1062–1068. doi:10.1111/j.1460-9568.2011.07604.x PubMedCrossRef

Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, van Praag H, Martone ME, Ellisman MH, Gage FH (2007) Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 10(6):727–734. doi:10.1038/nn1908 PubMedCrossRef

Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, Gage FH, Schinder AF (2008) Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 11(8):901–907. doi:10.1038/nn.2156 PubMedCentralPubMedCrossRef

Tronel S, Fabre A, Charrier V, Oliet SH, Gage FH, Abrous DN (2010) Spatial learning sculpts the dendritic arbor of adult-born hippocampal neurons. Proc Natl Acad Sci USA 107(17):7963–7968. doi:10.1073/pnas.0914613107 PubMedCentralPubMedCrossRef

Ullian EM, Sapperstein SK, Christopherson KS, Barres BA (2001) Control of synapse number by glia. Science 291(5504):657–661. doi:10.1126/science.291.5504.657291/5504/657 PubMedCrossRef

van Praag H, Christie BR, Sejnowski TJ, Gage FH (1999) Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA 96(23):13427–13431PubMedCentralPubMedCrossRef

van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415(6875):1030–1034. doi:10.1038/4151030a PubMedCrossRef

Ventura R, Harris KM (1999) Three-dimensional relationships between hippocampal synapses and astrocytes. J Neurosci 19(16):6897–6906PubMed

Vivar C, Potter MC, Choi J, Lee JY, Stringer TP, Callaway EM, Gage FH, Suh H, van Praag H (2012) Monosynaptic inputs to new neurons in the dentate gyrus. Nature Commun 3:1107. doi:10.1038/ncomms2101 CrossRef

Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6(8):626–640. doi:10.1038/nrn1722 PubMedCrossRef

Witcher MR, Kirov SA, Harris KM (2007) Plasticity of perisynaptic astroglia during synaptogenesis in the mature rat hippocampus. Glia 55(1):13–23. doi:10.1002/glia.20415 PubMedCrossRef

Witcher MR, Park YD, Lee MR, Sharma S, Harris KM, Kirov SA (2010) Three-dimensional relationships between perisynaptic astroglia and human hippocampal synapses. Glia 58(5):572–587. doi:10.1002/glia.20946 PubMedCentralPubMed

Zhang X, Zhang J, Chen C (2009) Long-term potentiation at hippocampal perforant path-dentate astrocyte synapses. Biochemical and biophysical research communications 383(3):326–330. doi:10.1016/j.bbrc.2009.04.005 PubMedCentralPubMedCrossRef

Zhao C, Teng EM, Summers RG Jr, Ming GL, Gage FH (2006) Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26(1):3–11. doi:10.1523/JNEUROSCI.3648-05.2006 PubMedCrossRef

Title: Pre-existing astrocytes form functional perisynaptic processes on neurons generated in the adult hippocampus
Authors: Marine Krzisch
Silvio G. Temprana
Lucas A. Mongiat
Jan Armida
Valentin Schmutz
Mari A. Virtanen
Jacqueline Kocher-Braissant
Rudolf Kraftsik
Laszlo Vutskits
Karl-Klaus Conzelmann
Matteo Bergami
Fred H. Gage
Alejandro F. Schinder
Nicolas Toni
Publication date: 01-07-2015
Publisher: Springer Berlin Heidelberg
Published in: Brain Structure and Function / Issue 4/2015
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-014-0768-y

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Pre-existing astrocytes form functional perisynaptic processes on neurons generated in the adult hippocampus

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