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Cited by 634Neurogenesis and neuroplasticity mechanismsTreatment of Major DepressionNerve injury and regeneration

TrkB Regulates Hippocampal Neurogenesis and Governs Sensitivity to Antidepressive Treatment

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Li, Yun, Luikart, Bryan W., Birnbaum, Shari, Chen, Jian, Kwon, Chang-Hyuk, Kernie, Steven G., Bassel-Duby, Rhonda, Parada, Luis F.·2008·Neuron
DOI 10.1016/j.neuron.2008.06.023PMC PMC2655199
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Abstract

Adult hippocampal neurogenesis is stimulated by chronic administration of antidepressants (ADs) and by voluntary exercise. Neural progenitor cells (NPCs) in the dentate gyrus (DG) that are capable of continuous proliferation and neuronal differentiation are the source of such structural plasticity. Here we report that mice lacking the receptor tyrosine kinase TrkB in hippocampal NPCs have impaired proliferation and neurogenesis. When exposed to chronic ADs or wheel-running, no increase in proliferation or neurogenesis is observed. Ablation of TrkB also renders these mice behaviorally insensitive to antidepressive treatment in depression- and anxiety-like paradigms. In contrast, mice lacking TrkB only in differentiated DG neurons display typical neurogenesis and respond normally to chronic ADs. Thus, our data establish an essential cell-autonomous role for TrkB in regulating hippocampal neurogenesis and behavioral sensitivity to antidepressive treatments, and support the notion that impairment of the neurogenic niche is an etiological factor for refractory responses to an antidepressive regimen.

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Research works printed but not linked: 63

  1. Alvarez-Buylla A Neurogenesis and plasticity in the CNS of adult birds Exp Neurol 1992 115 110 114 1728556
  2. Alvarez-Buylla A Lim DA For the long run: maintaining germinal niches in the adult brain Neuron 2004 41 683 686 15003168
  3. Barnabe-Heider F Miller FD Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways J Neurosci 2003 23 5149 5160 12832539 PMC6741181
  4. Berton O McClung CA Dileone RJ Krishnan V Renthal W Russo SJ Graham D Tsankova NM Bolanos CA Rios M Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress Science 2006 311 864 868 16469931
  5. Bremner JD Narayan M Anderson ER Staib LH Miller HL Charney DS Hippocampal volume reduction in major depression Am J Psychiatry 2000 157 115 118 10618023
  6. Bull ND Bartlett PF The adult mouse hippocampal progenitor is neurogenic but not a stem cell J Neurosci 2005 25 10815 10821 16306394 PMC6725873
  7. Chen ZY Jing D Bath KG Ieraci A Khan T Siao CJ Herrera DG Toth M Yang C McEwen BS Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior Science 2006 314 140 143 17023662 PMC1880880
  8. Choi MJ Kang RH Lim SW Oh KS Lee MS Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder Brain Res 2006 1118 176 182 16979146
  9. Coe CL Kramer M Czeh B Gould E Reeves AJ Kirschbaum C Fuchs E Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys Biol Psychiatry 2003 54 1025 1034 14625144
  10. Conti AC Cryan JF Dalvi A Lucki I Blendy JA cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs J Neurosci 2002 22 3262 3268 11943827 PMC6757540
  11. Czeh B Michaelis T Watanabe T Frahm J de Biurrun G van Kampen M Bartolomucci A Fuchs E Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine Proc Natl Acad Sci U S A 2001 98 12796 12801 11675510 PMC60133
  12. Egan MF Kojima M Callicott JH Goldberg TE Kolachana BS Bertolino A Zaitsev E Gold B Goldman D Dean M The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function Cell 2003 112 257 269 12553913
  13. Fagiolini A Kupfer DJ Is treatment-resistant depression a unique subtype of depression? Biol Psychiatry 2003 53 640 648 12706950
  14. Frazer A Pharmacology of antidepressants J Clin Psychopharmacol 1997 17 Suppl 1 2S 18S 9090573
  15. Gilbertson MW Shenton ME Ciszewski A Kasai K Lasko NB Orr SP Pitman RK Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma Nat Neurosci 2002 5 1242 1247 12379862 PMC2819093
  16. Gorski JA Balogh SA Wehner JM Jones KR Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice Neuroscience 2003 121 341 354 14521993
  17. He XP Kotloski R Nef S Luikart BW Parada LF McNamara JO Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model Neuron 2004 43 31 42 15233915
  18. Holick KA Lee DC Hen R Dulawa SC Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor Neuropsychopharmacology 2008 33 406 417 17429410
  19. Jakubs K Nanobashvili A Bonde S Ekdahl CT Kokaia Z Kokaia M Lindvall O Environment matters: synaptic properties of neurons born in the epileptic adult brain develop to reduce excitability Neuron 2006 52 1047 1059 17178407
  20. Jiang X Xu K Hoberman J Tian F Marko AJ Waheed JF Harris CR Marini AM Enoch MA Lipsky RH BDNF variation and mood disorders: a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects Neuropsychopharmacology 2005 30 1353 1361 15770238
  21. Karl A Schaefer M Malta LS Dorfel D Rohleder N Werner A A meta-analysis of structural brain abnormalities in PTSD Neurosci Biobehav Rev 2006 30 1004 1031 16730374
  22. Kempermann G Kuhn HG Gage FH More hippocampal neurons in adult mice living in an enriched environment Nature 1997 386 493 495 9087407
  23. Klein R Martin-Zanca D Barbacid M Parada LF Expression of the tyrosine kinase receptor gene trkB is confined to the murine embryonic and adult nervous system Development 1990 109 845 850 2171894
  24. Lee J Duan W Long JM Ingram DK Mattson MP Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats J Mol Neurosci 2000 15 99 108 11220789
  25. Lei L Laub F Lush M Romero M Zhou J Luikart B Klesse L Ramirez F Parada LF The zinc finger transcription factor Klf7 is required for TrkA gene expression and development of nociceptive sensory neurons Genes Dev 2005 19 1354 1364 15937222 PMC1142558
  26. Leuner B Gould E Shors TJ Is there a link between adult neurogenesis and learning? Hippocampus 2006 16 216 224 16421862
  27. Liebl DJ Klesse LJ Tessarollo L Wohlman T Parada LF Loss of brain-derived neurotrophic factor-dependent neural crest-derived sensory neurons in neurotrophin-4 mutant mice Proc Natl Acad Sci U S A 2000 97 2297 2302 10681461 PMC15795
  28. Lledo PM Alonso M Grubb MS Adult neurogenesis and functional plasticity in neuronal circuits Nat Rev Neurosci 2006 7 179 193 16495940
  29. Luikart BW Nef S Virmani T Lush ME Liu Y Kavalali ET Parada LF TrkB has a cell-autonomous role in the establishment of hippocampal Schaffer collateral synapses J Neurosci 2005 25 3774 3786 15829629 PMC6724922
  30. Lush ME Li Y Kwon CH Chen J Parada LF Neurofibromin is required for barrel formation in the mouse somatosensory cortex J Neurosci 2008 28 1580 1587 18272679 PMC2760344
  31. MacQueen GM Campbell S McEwen BS Macdonald K Amano S Joffe RT Nahmias C Young LT Course of illness, hippocampal function, and hippocampal volume in major depression Proc Natl Acad Sci U S A 2003 100 1387 1392 12552118 PMC298782
  32. Malberg JE Eisch AJ Nestler EJ Duman RS Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus J Neurosci 2000 20 9104 9110 11124987 PMC6773038
  33. Ming GL Song H Adult neurogenesis in the mammalian central nervous system Annu Rev Neurosci 2005 28 223 250 16022595
  34. Minichiello L Korte M Wolfer D Kuhn R Unsicker K Cestari V Rossi-Arnaud C Lipp HP Bonhoeffer T Klein R Essential role for TrkB receptors in hippocampus-mediated learning Neuron 1999 24 401 414 10571233
  35. Monteggia LM Luikart B Barrot M Theobold D Malkovska I Nef S Parada LF Nestler EJ Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors Biol Psychiatry 2007 61 187 197 16697351
  36. Morilak DA Frazer A Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders Int J Neuropsychopharmacol 2004 7 193 218 15003145
  37. Nakagawa S Kim JE Lee R Malberg JE Chen J Steffen C Zhang YJ Nestler EJ Duman RS Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein J Neurosci 2002 22 3673 3682 11978843 PMC6758358
  38. Neeper SA Gomez-Pinilla F Choi J Cotman CW Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain Brain Res 1996 726 49 56 8836544
  39. Nestler EJ Barrot M DiLeone RJ Eisch AJ Gold SJ Monteggia LM Neurobiology of depression Neuron 2002 34 13 25 11931738
  40. Nibuya M Nestler EJ Duman RS Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus J Neurosci 1996 16 2365 2372 8601816 PMC6578518
  41. Perera TD Coplan JD Lisanby SHC Lipira CM Arif M Carpio C Spitzer G Santarelli L Scharf B Hen R Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates J Neurosci 2007 27 4894 4901 17475797 PMC6672102
  42. Porsolt RD Chermat R Lenegre A Avril I Janvier S Steru L Use of the automated tail suspension test for the primary screening of psychotropic agents Arch Int Pharmacodyn Ther 1987 288 11 30 2889430
  43. Rios M Fan G Fekete C Kelly J Bates B Kuehn R Lechan RM Jaenisch R Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity Mol Endocrinol 2001 15 1748 1757 11579207
  44. Rossi C Angelucci A Costantin L Braschi C Mazzantini M Babbini F Fabbri ME Tessarollo L Maffei L Berardi N Caleo M Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment Eur J Neurosci 2006 24 1850 1856 17040481
  45. Saarelainen T Hendolin P Lucas G Koponen E Sairanen M MacDonald E Agerman K Haapasalo A Nawa H Aloyz R Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects J Neurosci 2003 23 349 357 12514234 PMC6742146
  46. 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 15689544 PMC6725966
  47. Salmon P Effects of physical exercise on anxiety, depression, and sensitivity to stress: a unifying theory Clin Psychol Rev 2001 21 33 61 11148895
  48. Santarelli L Saxe M Gross C Surget A Battaglia F Dulawa S Weisstaub N Lee J Duman R Arancio O Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants Science 2003 301 805 809 12907793
  49. Scharfman H Goodman J Macleod A Phani S Antonelli C Croll S Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats Exp Neurol 2005 192 348 356 15755552
  50. Scharfman HE Hen R Neuroscience. Is more neurogenesis always better? Science 2007 315 336 338 17234934 PMC2041961
  51. Schule C Zill P Baghai TC Eser D Zwanzger P Wenig N Rupprecht R Bondy B Brain-derived neurotrophic factor Val66Met polymorphism and dexamethasone/CRH test results in depressed patients Psychoneuroendocrinology 2006 31 1019 1025 16890377
  52. Seaberg RM van der Kooy D Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors J Neurosci 2002 22 1784 1793 11880507 PMC6758891
  53. Sheline YI Gado MH Kraemer HC Untreated depression and hippocampal volume loss Am J Psychiatry 2003 160 1516 1518 12900317
  54. Shirayama Y Chen AC Nakagawa S Russell DS Duman RS Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression J Neurosci 2002 22 3251 3261 11943826 PMC6757539
  55. Smith ME Bilateral hippocampal volume reduction in adults with posttraumatic stress disorder: a meta-analysis of structural MRI studies Hippocampus 2005 15 798 807 15988763
  56. Soriano P Generalized lacZ expression with the ROSA26 Cre reporter strain Nat Genet 1999 21 70 71 9916792
  57. Svenningsson P Chergui K Rachleff I Flajolet M Zhang X El Yacoubi M Vaugeois JM Nomikos GG Greengard P Alterations in 5-HT1B receptor function by p11 in depression-like states Science 2006 311 77 80 16400147
  58. Thase ME Rush AJ B FE K DJ Treatment-resistant depression Psychopharmacology: The Fourth Generation of Progress 1995 New York Raven Press 1081 1098
  59. Wang JW David DJ Monckton JE Battaglia F Hen R Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells J Neurosci 2008a 28 1374 1384 18256257 PMC6671574
  60. Wang JW Dranovsky A Hen R The when and where of BDNF and the antidepressant response Biol Psychiatry 2008b 63 640 641 18329441
  61. Yu TS Dandekar M Monteggia LM Parada LF Kernie SG Temporally regulated expression of Cre recombinase in neural stem cells Genesis 2005 41 147 153 15789426
  62. Zhao C Deng W Gage FH Mechanisms and functional implications of adult neurogenesis Cell 2008 132 645 660 18295581
  63. Zhou XF Parada LF Soppet D Rush RA Distribution of trkB tyrosine kinase immunoreactivity in the rat central nervous system Brain Res 1993 622 63 70 8242385

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Sorted by citations

Authors
Li, Y., Luikart, B. W., Birnbaum, S., Chen, J., Kwon, C.-H., Kernie, S. G., Bassel-Duby, R., & Parada, L. F.
Affiliations
The University of Texas Southwestern Medical Center (US)
Corresponding author
Parada, Luis F.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2008-08
Volume
59
Issue
3
Pages
399-412
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2008.06.023
PMC
PMC2655199
OpenAlex
W2091927578
Cited by
634
References
9
Citations by year
2026: 13 · 2025: 16 · 2024: 24 · 2023: 19 · 2022: 25 · 2021: 39 · 2020: 29 · 2019: 23 · 2018: 42 · 2017: 34 · 2016: 35 · 2015: 47 · 2014: 45 · 2013: 45 · 2012: 53
FWCI
14.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (P50 MH66172, P50MH066172)
  • National Institute of Neurological Disorders and Stroke (R37NS033199)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (K08HD001470)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
Keywords
TrkB receptor, hippocampal neurogenesis, adult neurogenesis, antidepressant sensitivity, neural progenitor cells, dentate gyrus, voluntary wheel running, depression-like behavior, anxiety-like behavior, antidepressant resistance, neurogenic niche
MeSH terms
Animals, Animals, Newborn, Antidepressive Agents, Behavior, Animal, Cell Differentiation, Enzyme-Linked Immunosorbent Assay, Estrogen Antagonists, Flow Cytometry, Hippocampus, Intermediate Filament Proteins, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Neurons, Tamoxifen, Brain-Derived Neurotrophic Factor, Receptor, trkB, Cell Proliferation, Green Fluorescent Proteins, Mice, Adult Stem Cells, Nestin

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