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Critical periods regulating the circuit integration of adult-born hippocampal neurons

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Abstract

The dentate gyrus (DG) in the adult brain maintains the capability to generate new granule neurons throughout life. Neural stem cell-derived new-born neurons emerge to play key functions in the way information is processed in the DG and then conveyed to the CA3 hippocampal area, yet accumulating evidence indicates that both the maturation process and the connectivity pattern of new granule neurons are not prefigured but can be modulated by the activity of local microcircuits and, on a network level, by experience. Although most of the activity- and experience-dependent changes described so far appear to be restricted to critical periods during the development of new granule neurons, it is becoming increasingly clear that the surrounding circuits may play equally key roles in accommodating and perhaps fostering, these changes. Here, we review some of the most recent insights into this almost unique form of plasticity in the adult brain by focusing on those critical periods marked by pronounced changes in structure and function of the new granule neurons and discuss how the activity of putative synaptic partners may contribute to shape the circuit module in which new neurons become finally integrated.

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Abbreviations

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BDNF:

Brain-derived neurotrophic factor

CREB:

cAMP response element binding protein

DG:

Dentate gyrus

EC:

Entorhinal cortex

EE:

Enriched environment

GABA:

γ-Aminobutyric acid

LTP:

Long-term potentiation

ML:

Molecular layer

NMDA:

N-methyl-D-aspartate

NR2B:

N-methyl-D-aspartate receptor subtype 2B

POMC:

Pro-opiomelanocortin

References

  • Alvarez DD, Giacomini D, Yang SM, Trinchero MF, Temprana SG, Buttner KA, Beltramone N, Schinder AF (2016) A disynaptic feedback network activated by experience promotes the integration of new granule cells. Science 354:459–465

    Article  CAS  PubMed  Google Scholar 

  • Beining M, Jungenitz T, Radic T, Deller T, Cuntz H, Jedlicka P, Schwarzacher SW (2017) Adult-born dentate granule cells show a critical period of dendritic reorganization and are distinct from developmentally born cells. Brain Struct Funct 222:1427–1446

    Article  PubMed  Google Scholar 

  • Bergami M, Rimondini R, Santi S, Blum R, Gotz M, Canossa M (2008) Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proc Natl Acad Sci U S A 105:15570–15575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bergami M, Masserdotti G, Temprana SG, Motori E, Eriksson TM, Gobel J, Yang SM, Conzelmann KK, Schinder AF, Gotz M, Berninger B (2015) A critical period for experience-dependent remodeling of adult-born neuron connectivity. Neuron 85:710–717

    Article  CAS  PubMed  Google Scholar 

  • Bruel-Jungerman E, Davis S, Rampon C, Laroche S (2006) Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J Neurosci 26:5888–5893

    Article  CAS  PubMed  Google Scholar 

  • Campbell NR, Fernandes CC, Halff AW, Berg DK (2010) Endogenous signaling through alpha7-containing nicotinic receptors promotes maturation and integration of adult-born neurons in the hippocampus. J Neurosci 30:8734–8744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chancey JH, Adlaf EW, Sapp MC, Pugh PC, Wadiche JI, Overstreet-Wadiche LS (2013) GABA depolarization is required for experience-dependent synapse unsilencing in adult-born neurons. J Neurosci 33:6614–6622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chancey JH, Poulsen DJ, Wadiche JI, Overstreet-Wadiche L (2014) Hilar mossy cells provide the first glutamatergic synapses to adult-born dentate granule cells. J Neurosci 34:2349–2354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Danielson NB, Kaifosh P, Zaremba JD, Lovett-Barron M, Tsai J, Denny CA, Balough EM, Goldberg AR, Drew LJ, Hen R, Losonczy A, Kheirbek MA (2016) Distinct contribution of adult-born hippocampal granule cells to context encoding. Neuron 90:101–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Danielson NB, Turi GF, Ladow M, Chavlis S, Petrantonakis PC, Poirazi P, Losonczy A (2017) In vivo imaging of dentate gyrus mossy cells in behaving mice. Neuron 93(552–559):e554

    Google Scholar 

  • 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 U S A 110:E1152–E1161

  • Dieni CV, Panichi R, Aimone JB, Kuo CT, Wadiche JI, Overstreet-Wadiche L (2016) Low excitatory innervation balances high intrinsic excitability of immature dentate neurons. Nat Commun 7:11313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donato F, Rompani SB, Caroni P (2013) Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature 504:272–276

    Article  CAS  PubMed  Google Scholar 

  • Drew LJ, Kheirbek MA, Luna VM, Denny CA, Cloidt MA, Wu MV, Jain S, Scharfman HE, Hen R (2016) Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons. Hippocampus 26:763–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duveau V, Laustela S, Barth L, Gianolini F, Vogt KE, Keist R, Chandra D, Homanics GE, Rudolph U, Fritschy JM (2011) Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis. Eur J Neurosci 34:362–373

    Article  PubMed  PubMed Central  Google Scholar 

  • Esposito MS, Piatti VC, Laplagne DA, Morgenstern NA, Ferrari CC, Pitossi FJ, Schinder AF (2005) Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci 25:10074–10086

    Article  CAS  PubMed  Google Scholar 

  • Ge S, Goh EL, Sailor KA, Kitabatake Y, Ming GL, Song H (2006) GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439:589–593

    Article  CAS  PubMed  Google Scholar 

  • 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 54:559–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goncalves JT, Bloyd CW, Shtrahman M, Johnston ST, Schafer ST, Parylak SL, Tran T, Chang T, Gage FH (2016) In vivo imaging of dendritic pruning in dentate granule cells. Nat Neurosci 19:788–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • GoodSmith D, Chen X, Wang C, Kim SH, Song H, Burgalossi A, Christian KM, Knierim JJ (2017) Spatial representations of granule cells and mossy cells of the dentate gyrus. Neuron 93(677–690):e675

    Google Scholar 

  • Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999) Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2:260–265

    Article  CAS  PubMed  Google Scholar 

  • 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 15:1700–1706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heigele S, Sultan S, Toni N, Bischofberger J (2016) Bidirectional GABAergic control of action potential firing in newborn hippocampal granule cells. Nat Neurosci 19:263–270

    Article  CAS  PubMed  Google Scholar 

  • Jagasia R, Steib K, Englberger E, Herold S, Faus-Kessler T, Saxe M, Gage FH, Song H, Lie DC (2009) GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J Neurosci 29:7966–7977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10:355–362

    Article  CAS  PubMed  Google Scholar 

  • Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386:493–495

    Article  CAS  PubMed  Google Scholar 

  • Kheirbek MA, Tannenholz L, Hen R (2012) NR2B-dependent plasticity of adult-born granule cells is necessary for context discrimination. J Neurosci 32:8696–8702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kitamura T, Saitoh Y, Murayama A, Sugiyama H, Inokuchi K (2010) 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 3:13

    Article  PubMed  PubMed Central  Google Scholar 

  • Kumamoto N, Gu Y, Wang J, Janoschka S, Takemaru K, Levine J, Ge S (2012) A role for primary cilia in glutamatergic synaptic integration of adult-born neurons. Nat Neurosci 15(399–405):S391

    Google Scholar 

  • 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:e409

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee SW, Clemenson GD, Gage FH (2012) New neurons in an aged brain. Behav Brain Res 227:497–507

    Article  PubMed  Google Scholar 

  • Li Y, Stam FJ, Aimone JB, Goulding M, Callaway EM, Gage FH (2013) Molecular layer perforant path-associated cells contribute to feed-forward inhibition in the adult dentate gyrus. Proc Natl Acad Sci U S A 110:9106–9111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lopez CM, Pelkey KA, Chittajallu R, Nakashiba T, Toth K, Tonegawa S, McBain CJ (2012) Competition from newborn granule cells does not drive axonal retraction of silenced old granule cells in the adult hippocampus. Front Neural Circuits 6:85

  • Maffei A, Turrigiano G (2008) The age of plasticity: developmental regulation of synaptic plasticity in neocortical microcircuits. Prog Brain Res 169:211–223

    Article  PubMed  Google Scholar 

  • 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 335:1238–1242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Markwardt SJ, Dieni CV, Wadiche JI, Overstreet-Wadiche L (2011) Ivy/neurogliaform interneurons coordinate activity in the neurogenic niche. Nat Neurosci 14:1407–1409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McAvoy KM, Scobie KN, Berger S, Russo C, Guo N, Decharatanachart P, Vega-Ramirez H, Miake-Lye S, Whalen M, Nelson M, Bergami M, Bartsch D, Hen R, Berninger B, Sahay A (2016) Modulating neuronal competition dynamics in the dentate gyrus to rejuvenate aging memory circuits. Neuron 91:1356–1373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mongiat LA, Esposito MS, Lombardi G, Schinder AF (2009) Reliable activation of immature neurons in the adult hippocampus. PLoS ONE 4:e5320

    Article  PubMed  PubMed Central  Google Scholar 

  • Mu Y, Zhao C, Toni N, Yao J, Gage FH (2015) Distinct roles of NMDA receptors at different stages of granule cell development in the adult brain. eLife 4:e07871

    Article  PubMed  PubMed Central  Google Scholar 

  • Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL, McHugh TJ, Rodriguez Barrera V, Chittajallu R, Iwamoto KS, McBain CJ, Fanselow MS, Tonegawa S (2012) Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 149:188–201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Piatti VC, Davies-Sala MG, Esposito MS, Mongiat LA, Trinchero MF, Schinder AF (2011) The timing for neuronal maturation in the adult hippocampus is modulated by local network activity. J Neurosci 31:7715–7728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pieraut S, Gounko N, Sando R 3rd, Dang W, Rebboah E, Panda S, Madisen L, Zeng H, Maximov A (2014) Experience-dependent remodeling of basket cell networks in the dentate gyrus. Neuron 84:107–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Restivo L, Niibori Y, Mercaldo V, Josselyn SA, Frankland PW (2015) Development of adult-generated cell connectivity with excitatory and inhibitory cell populations in the hippocampus. J Neurosci 35:10600–10612

    Article  CAS  PubMed  Google Scholar 

  • 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 472:466–470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Senzai Y, Buzsaki G (2017) Physiological properties and behavioral correlates of hippocampal granule cells and mossy cells. Neuron 93:691–704 e695

    Article  CAS  PubMed  Google Scholar 

  • Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7:483–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song J, Sun J, Moss J, Wen Z, Sun GJ, Hsu D, Zhong C, Davoudi H, Christian KM, Toni N, Ming GL, Song H (2013) Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus. Nat Neurosci 16:1728–1730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stone SS, Teixeira CM, Zaslavsky K, Wheeler AL, Martinez-Canabal A, Wang AH, Sakaguchi M, Lozano AM, Frankland PW (2011) Functional convergence of developmentally and adult-generated granule cells in dentate gyrus circuits supporting hippocampus-dependent memory. Hippocampus 21:1348–1362

    Article  PubMed  Google Scholar 

  • Sultan S, Li L, Moss J, Petrelli F, Casse F, Gebara E, Lopatar J, Pfrieger FW, Bezzi P, Bischofberger J, Toni N (2015) Synaptic integration of adult-born hippocampal neurons is locally controlled by astrocytes. Neuron 88:957–972

    Article  CAS  PubMed  Google Scholar 

  • Sun W, Winseck A, Vinsant S, Park OH, Kim H, Oppenheim RW (2004) Programmed cell death of adult-generated hippocampal neurons is mediated by the proapoptotic gene Bax. J Neurosci 24:11205–11213

    Article  CAS  PubMed  Google Scholar 

  • Sun GJ, Sailor KA, Mahmood QA, Chavali N, Christian KM, Song H, Ming GL (2013) Seamless reconstruction of intact adult-born neurons by serial end-block imaging reveals complex axonal guidance and development in the adult hippocampus. J Neurosci 33:11400–11411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takesian AE, Hensch TK (2013) Balancing plasticity/stability across brain development. Prog Brain Res 207:3–34

    Article  PubMed  Google Scholar 

  • 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 442:929–933

    Article  CAS  PubMed  Google Scholar 

  • Tashiro A, Makino H, Gage FH (2007) Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J Neurosci 27:3252–3259

    Article  CAS  PubMed  Google Scholar 

  • Temprana SG, Mongiat LA, Yang SM, Trinchero MF, Alvarez DD, Kropff E, Giacomini D, Beltramone N, Lanuza GM, Schinder AF (2015) Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells. Neuron 85:116–130

    Article  CAS  PubMed  Google Scholar 

  • 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 10:727–734

    Article  CAS  PubMed  Google Scholar 

  • 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 11:901–907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tozuka Y, Fukuda S, Namba T, Seki T, Hisatsune T (2005) GABAergic excitation promotes neuronal differentiation in adult hippocampal progenitor cells. Neuron 47:803–815

    Article  CAS  PubMed  Google Scholar 

  • van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270

    Article  PubMed  Google Scholar 

  • 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. Nat Commun 3:1107

    Article  PubMed  PubMed Central  Google Scholar 

  • Vivar C, Peterson BD, van Praag H (2016) Running rewires the neuronal network of adult-born dentate granule cells. NeuroImage 131:29–41

    Article  PubMed  Google Scholar 

  • Wang S, Scott BW, Wojtowicz JM (2000) Heterogenous properties of dentate granule neurons in the adult rat. J Neurobiol 42:248–257

    Article  CAS  PubMed  Google Scholar 

  • Yasuda M, Johnson-Venkatesh EM, Zhang H, Parent JM, Sutton MA, Umemori H (2011) Multiple forms of activity-dependent competition refine hippocampal circuits in vivo. Neuron 70:1128–1142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 26:3–11

    Article  CAS  PubMed  Google Scholar 

  • Zhao C, Jou J, Wolff LJ, Sun H, Gage FH (2014) Spine morphogenesis in newborn granule cells is differentially regulated in the outer and middle molecular layers. J Comp Neurol 522:2756–2766

    Article  PubMed  PubMed Central  Google Scholar 

  • Zuccaro E, Bergami M, Vignoli B, Bony G, Pierchala BA, Santi S, Cancedda L, Canossa M (2014) Polarized expression of p75(NTR) specifies axons during development and adult neurogenesis. Cell Rep 7:138–152

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the European Research Council (ERC-StG-2015, grant number 67844) to M.B.

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Authors and Affiliations

  1. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and University Hospital of Cologne, Joseph-Stelzmann-Straße 26, D-50931, Cologne, Germany

    Hannah Maria Jahn & Matteo Bergami

  2. Center for Molecular Medicine (CMMC), University of Cologne, Robert-Koch-Str. 21, D-50931, Cologne, Germany

    Matteo Bergami

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  1. Hannah Maria Jahn
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Correspondence to Matteo Bergami.

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Jahn, H.M., Bergami, M. Critical periods regulating the circuit integration of adult-born hippocampal neurons. Cell Tissue Res 371, 23–32 (2018). https://doi.org/10.1007/s00441-017-2677-x

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