Abstract
New neurons are continuously generated from resident pools of neural stem and precursor cells (NSPCs) in the adult brain. There are multiple pathways through which adult neurogenesis is regulated, and here we review the role of the N-methyl-d-aspartate receptor (NMDAR) in regulating the proliferation of NSPCs in the adult hippocampus. Hippocampal-dependent learning tasks, enriched environments, running, and activity-dependent synaptic plasticity, all potently up-regulate hippocampal NSPC proliferation. We first consider the requirement of the NMDAR in activity-dependent synaptic plasticity, and the role the induction of synaptic plasticity has in regulating NSPCs and newborn neurons. We address how specific NMDAR agonists and antagonists modulate proliferation, both in vivo and in vitro, and then review the evidence supporting the hypothesis that NMDARs are present on NSPCs. We believe it is important to understand the mechanisms underlying the activation of adult neurogenesis, given the potential that endogenous stem cell populations have for repopulating the hippocampus with functional new neurons. In conditions such as age-related memory decline, neurodegeneration and psychiatric disease, mature neurons are lost or become defective; as such, stimulating adult neurogenesis may provide a therapeutic strategy to overcome these conditions.
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Richards LJ, Kilpatrick TJ, Bartlett PF. De novo generation of neuronal cells from the adult-mouse brain. Proc Natl Acad Sci USA, 1992, 89: 8591–8595
Reynolds BA, Weiss S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol, 1996, 175: 1–13
Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell, 2008, 132: 645–660
Mongiat LA, Schinder AF. Adult neurogenesis and the plasticity of the dentate gyrus network. Eur J Neurosci, 2011, 33: 1055–1061
Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci, 1999, 2: 260–265
van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci, 1999, 2: 266–270
Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature, 1997, 386: 493–495
Nilsson M, Perfilieva E, Johansson U, Orwar O, Eriksson PS. Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J Neurobiol, 1999, 39: 569–578
Bruel-Jungerman E, Davis S, Rampon C, Laroche S. Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J Neurosci, 2006, 26: 5888–5893
van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning and long-term potentiation in mice. Proc Natl Acad Sci USA, 1999, 96: 13427–13431
Nicoll RA, Roche KW. Long-term potentiation: peeling the onion. Neuropharmacology, 2013, 74: 18–22
Kameda M, Taylor CJ, Walker TL, Black DM, Abraham WC, Bartlett PF. Activation of latent precursors in the hippocampus is dependent on long-term potentiation. Transl Psychiat, 2012, 2: e72
Kitamura T, Saitoh Y, Murayama A, Sugiyama H, Inokuchi K. LTP induction within a narrow critical period of immature stages enhances the survival of newly generated neurons in the adult rat dentate gyrus. Mol Brain, 2010, 3: 13
Wang S, Scott BW, Wojtowicz JM. Heterogenous properties of dentate granule neurons in the adult rat. J Neurobiol, 2000, 42: 248–257
Schmidt-Hieber C, Jonas P, Bischofberger J. Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus. Nature, 2004, 429: 184–187
Massa F, Koelh M, Wiesner T, Grosjean N, Revest JM, Piazza PV, Abrous DN, Oliet SHR. Conditional reduction of adult neurogenesis impairs bidirectional hippocampal synaptic plasticity. Proc Natl Acad Sci USA, 2011, 108: 6644–6649
Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci, 2010, 11: 339–350
Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL, Mchugh TJ, Barrera VR, Chittajallu R, Iwamoto KS, Mcbain CJ, Fanselow MS, Tonegawa S. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell, 2012, 149: 188–201
Vukovic J, Borlikova GG, Ruitenberg MJ, Robinson GJ, Sullivan RKP, Walker TL, Bartlett PF. Immature doublecortin-positive hippocampal neurons are important for learning but not for remembering. J Neurosci, 2013, 33: 6603–6613
Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci, 2007, 10: 1110–1115
Petrik D, Lagace DC, Eisch AJ. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology, 2011, 62: 21–34
Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature, 2011, 476: 458–461
Walker TL, White A, Black DM, Wallace RH, Sah P, Bartlett PF. Latent stem and progenitor cells in the hippocampus are activated by neural excitation. J Neurosci, 2008, 28: 5240–5247
Taylor CJ, Jhaveri DJ, Bartlett PF. The therapeutic potential of endogenous hippocampal stem cells for the treatment of neurological disorders. Front Cell Neurosci, 2013, 7: 5
Jhaveri DJ, Taylor CJ, Bartlett PF. Activation of different neural precursor populations in the adult hippocampus: does this lead to new neurons with discrete functions? Dev Neurobiol, 2012, 72: 1044–1058
Bergami M, Berninger B. A fight for survival: the challenges faced by a newborn neuron integrating in the adult hippocampus. Dev Neurobiol, 2012, 72: 1016–1031
Lugert S, Vogt M, Tchorz JS, Muller M, Giachino C, Taylor V. Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1 (high) intermediate progenitors. Nat Comm, 2012, 3: 670–670
Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Gotz M, Haas CA, Kempermann G, Taylor V, Giachino C. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell, 2010, 6: 445–456
Bonaguidi MA, Wheeler MA, Shapiro JS, Stadel RP, Sun GJ, Ming GL, Song H. In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell, 2011, 145: 1142–1155
von Bohlen und Halbach O. Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus. Cell Tissue Res, 2011, 345: 1–19
Bull ND, Bartlett PF. The adult mouse hippocampal progenitor is neurogenic but not a stem cell. J Neurosci, 2005, 25: 10815–10821
Lledo PM, Alonso M, Grubb MS. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci, 2006, 7: 179–193
Ming GL, Song HJ. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron, 2011, 70: 687–702
vanPraag H, Shubert T, Zhao CM, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci, 2005, 25: 8680–8685
van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci, 2000, 1: 191–198
Ramón y Cajal S. The Croonian Lecture: La Fine Structure des Centres Nerveux. Proc Natl Acad Sci USA, 1894, 55: 444–468
Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron, 2004, 44: 5–21
Collingridge GL, Kehl SJ, McLennan H. Excitatory amino-acids in synaptic transmission in the Schaffer collateral commissural pathway of the rat hippocampus. J Physiol, 1983, 334: 33–46
Johnston D, Williams S, Jaffe D, Gray R. NMDA-receptor-independent long-term potentiation. Ann Rev Physiol, 1992, 54: 489–505
Traynelis SF, Wollmuth LP, Mcbain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev, 2010, 62: 405–496
Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci, 2013, 14: 383–400
Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol, 2001, 11: 327–335
Collingridge GL, Bliss TVP. NMDA receptors-their role in long-term potentiation. Trends Neurosci, 1987, 10: 288–293
Buzsaki G. Theta oscillations in the hippocampus. Neuron, 2002, 33: 325–340
Larson J, Lynch G. Role of N-methyl-D-aspartate receptors in the induction of synaptic potentiation by burst stimulation patterned after the hippocampal θ rhythm. Brain Res, 1988, 441: 111–118
Harris EW, Ganong AH, Cotman CW. Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors. Brain Res, 1984, 323: 132–137
Morris RGM, Anderson E, Lynch GS, Baudry M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-d-aspartate receptor antagonist, AP5. Nature, 1986, 319: 774–776
Lynch G, Larson J, Kelso S, Barrionuevo G, Schottler F. Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature, 1983, 305: 719–721
Malinow R, Schulman H, Tsien RW. Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science, 1989, 245: 862–866
Silva AJ, Stevens CF, Tonegawa S, Wang YY. Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase-II mutant mice. Science, 1992, 257: 201–206
Wang JH, Feng DP. Postsynaptic protein-kinase-C essential to induction and maintenance of long-term potentiation in the hippocampal CA1 region. Proc Natl Acad Sci USA, 1992, 89: 2576–2580
Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ. Deficient long-term-memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell, 1994, 79: 59–68
Chun SK, Sun W, Park JJ, Jung MW. Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus. Neurobiol Learn Mem, 2006, 86: 322–329
Hartmann M, Heumann R, Lessmann V. Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J, 2001, 20: 5887–5897
Neugebauer F, Korz V, Frey JU. Modulation of extracellular monoamine transmitter concentrations in the hippocampus after weak and strong tetanization of the perforant path in freely moving rats. Brain Res, 2009, 1273: 29–38
Sairanen M, Lucas G, Ernfors P, Castren M, Castren E. Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci, 2005, 25: 1089–1094
Jhaveri DJ, Mackay EW, Hamlin AS, Marathe SV, Nandam LS, Vaidya VA, Bartlett PF. Norepinephrine directly activates adult hippocampal precursors via beta(3)-adrenergic receptors. J Neurosci, 2010, 30: 2795–2806
Babu H, Ramirez-Rodriguez G, Fabel K, Bischofberger J, Kempermann G. Synaptic network activity induces neuronal differentiation of adult hippocampal precursor cells through BDNF signaling. Front Neurosci, 2009, 3: 49
Tashiro A, Sandler VM, Toni N, Zhao C, Gage FH. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature, 2006, 442: 929–933
Ohkawa N, Saitoh Y, Tokunaga E, Nihonmatsu I, Ozawa F, Murayama A, Shibata F, Kitamura T, Inokuchi K. Spine formation pattern of adult-born neurons is differentially modulated by the induction timing and location of hippocampal plasticity. PLoS ONE, 2012, 7: e45270
Cameron HA, McEwen BS, Gould E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci, 1995, 15: 4687–4692
Kitayama T, Yoneyama M, Yoneda Y. Possible regulation by N-methyl-D-aspartate receptors of proliferative progenitor cells expressed in adult mouse hippocampal dentate gyrus. J Neurochem, 2003, 84: 767–780
Nacher J, Rosell DR, Alonso-Llosa G, Mcewen BS. NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci, 2001, 13: 512–520
Nacher J, Alonso-Llosa G, Rosell DR, Mcewen BS. NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging, 2003, 24: 273–284
Hu M, Sun YJ, Zhou QG, Chen L, Hu Y, Luo CX, Wu JY, Xu JS, Li LX, Zhu DY. Negative regulation of neurogenesis and spatial memory by NR2B-containing NMDA receptors. J Neurochem, 2008, 106: 1900–1913
Joo JY, Kim BW, Lee JS, Park JY, Kim S, Yun YJ, Lee SH, Lee SH, Rhim H, Son H. Activation of NMDA receptors increases proliferation and differentiation of hippocampal neural progenitor cells. J Cell Sci, 2007, 120: 1358–1370
Petrus DS, Fabel K, Kronenberg G, Winter C, Steiner B, Kempermann G. NMDA and benzodiazepine receptors have synergistic and antagonistic effects on precursor cells in adult hippocampal neurogenesis. Eur J Neurosci, 2009, 29: 244–252
Bursztajn S, Falls WA, Berman SA, Friedman MJ. Cell proliferation in the brains of NMDAR NR1 transgenic mice. Brain Res, 2007, 1172: 10–20
Kitayama T, Mishina M, Sugiyama H. Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptor epsilon 1 subunit. Neurosci Res, 2003, 47: 55–63
Kitayama T, Yoneyama M, Tamaki K, Yoneda Y. Regulation of neuronal differentiation by N-methyl-D-aspartate receptors expressed in neural progenitor cells isolated from adult mouse hippocampus. J Neurosci Res, 2004, 76: 599–612
Deisseroth K, Singla S, Toda H, Monje M, Palmer TD, Malenka RC. Excitation-neurogenesis coupling in adult neural stem/progenitor cells. Neuron, 2004, 42: 535–552
Li M, Zhang DQ, Wang XZ, Xu TJ. NR2B-containing NMDA receptors promote neural progenitor cell proliferation through CaMKIV/CREB pathway. Biochem Biophys Res Comm, 2011, 411: 667–672
Nacher J, Varea E, Blasco-Ibanez JM, Gomez-Climent MA, Castillo-Gomez E, Crespo C, Martinez-Guijarro FJ, Mcewen BS. N-methyl-D-aspartate receptor expression during adult neurogenesis in the rat dentate gyrus. Neurosci, 2007, 144: 855–864
Volbracht C, Van Beek J, Zhu C, Blomgren K, Leist M. Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity. Eur J Neurosci, 2006, 23: 2611–2622
Maekawa M, Namba T, Suzuki E, Yuasa S, Kohsaka S, Uchino S. NMDA receptor antagonist memantine promotes cell proliferation and production of mature granule neurons in the adult hippocampus. Neurosci Res, 2009, 63: 259–266
Namba T, Maekawa M, Yuasa S, Kohsaka S, Uchino S. The Alzheimer’s disease drug memantine increases the number of radial glia-like progenitor cells in adult hippocampus. Glia, 2009, 57: 1082–1090
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Taylor, C.J., He, R. & Bartlett, P.F. The role of the N-methyl-d-aspartate receptor in the proliferation of adult hippocampal neural stem and precursor cells. Sci. China Life Sci. 57, 403–411 (2014). https://doi.org/10.1007/s11427-014-4637-y
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DOI: https://doi.org/10.1007/s11427-014-4637-y