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BDNF effects on dendritic spine morphology and hippocampal function

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Abstract

Neurotrophins, including brain-derived neurotrophic factor (BDNF), are expressed in the hippocampus, as well as their precursors, the pro-neurotrophins. The neurotrophins signal through specific tyrosine kinase receptors and the low affinity receptor p75NTR. Moreover, the pro-neurotrophins are considered to be biologically active by signaling through specific receptors. The neurotrophins, especially BDNF, are involved in processes related to learning and memory. Furthermore, it is thought that BDNF also plays a crucial role in major depression. This points to a role of BDNF as a central regulator of neuronal plasticity within the postnatal hippocampus. Morphological correlates of neuronal plasticity are changes on the level of the dendritic spines and, at least in the dentate gyrus of the hippocampus, on the level of adult neurogenesis. Specific changes in dendritic spines as well as in adult hippocampal neurogenesis can be seen in the context of several forms of learning and memory, and it is known that depression is accompanied by declines in the rate of adult neurogenesis and in spine densities. The possible roles of BDNF in neuronal plasticity within the hippocampus are highlighted in this review by focusing on the morphological components of neuronal plasticity.

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References

  • Alcantara S, Frisen J, del Rio JA, Soriano E, Barbacid M, Silos-Santiago I (1997) TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death. J Neurosci 17:3623–3633

    Article  PubMed  CAS  Google Scholar 

  • Alonso M, Medina JH, Pozzo-Miller L (2004) ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem 11:172–178

    Article  PubMed  PubMed Central  Google Scholar 

  • Altar CA (1999) Neurotrophins and depression. Trends Pharmacol Sci 20:59–61

    Article  PubMed  CAS  Google Scholar 

  • Altschuler RA (1979) Morphometry of the effect of increased experience and training on synaptic density in area CA3 of the rat hippocampus. J Histochem Cytochem 27:1548–1550

    Article  PubMed  CAS  Google Scholar 

  • Angelucci F, Brene S, Mathe AA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 10:345–352

    Article  PubMed  CAS  Google Scholar 

  • Bahi A, Dreyer JL (2012) Hippocampus-specific deletion of tissue plasminogen activator “tPA” in adult mice impairs depression- and anxiety-like behaviors. Eur Neuropsychopharmacol 22:672–682

    Article  PubMed  CAS  Google Scholar 

  • Banerjee R, Ghosh AK, Ghosh B, Bhattacharyya S, Mondal AC (2013) Decreased mRNA and protein expression of BDNF, NGF, and their receptors in the hippocampus from suicide: an analysis in human Postmortem brain. Clin Med Insights Pathol 6:1–11

    Article  PubMed  PubMed Central  Google Scholar 

  • Barbacid M (1994) The Trk family of neurotrophin receptors. J Neurobiol 25:1386–1403

    Article  PubMed  CAS  Google Scholar 

  • Barker PA (1998) p75NTR: a study in contrasts. Cell Death Differ 5:346–356

    Article  PubMed  CAS  Google Scholar 

  • Barrett GL, Greferath U, Barker PA, Trieu J, Bennie A (2005) Co-expression of the P75 neurotrophin receptor and neurotrophin receptor-interacting melanoma antigen homolog in the mature rat brain. Neuroscience 133:381–392

    Article  PubMed  CAS  Google Scholar 

  • Becker N, Wierenga CJ, Fonseca R, Bonhoeffer T, Nagerl UV (2008) LTD induction causes morphological changes of presynaptic boutons and reduces their contacts with spines. Neuron 60:590–597

    Article  PubMed  CAS  Google Scholar 

  • Bernabeu RO, Longo FM (2010) The p75 neurotrophin receptor is expressed by adult mouse dentate progenitor cells and regulates neuronal and non-neuronal cell genesis. BMC Neurosci 11:136

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39

    Article  PubMed  CAS  Google Scholar 

  • Bliss TV, Lomo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232:331–356

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boitard C, Etchamendy N, Sauvant J, Aubert A, Tronel S, Marighetto A, Laye S, Ferreira G (2012) Juvenile, but not adult exposure to high-fat diet impairs relational memory and hippocampal neurogenesis in mice. Hippocampus 22:2095–2100

    Article  PubMed  CAS  Google Scholar 

  • Bruel-Jungerman E, Laroche S, Rampon C (2005) New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur J Neurosci 21:513–521

    Article  PubMed  Google Scholar 

  • Burghardt PR, Fulk LJ, Hand GA, Wilson MA (2004) The effects of chronic treadmill and wheel running on behavior in rats. Brain Res 1019:84–96

    Article  PubMed  CAS  Google Scholar 

  • Cao B, Bauer IE, Sharma AN, Mwangi B, Frazier T, Lavagnino L, Zunta-Soares GB, Walss-Bass C, Glahn DC, Kapczinski F, Nielsen DA, Soares JC (2016) Reduced hippocampus volume and memory performance in bipolar disorder patients carrying the BDNF val66met met allele. J Affect Disord 198:198–205

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Castren E, Rantamaki T (2008) Neurotrophins in depression and antidepressant effects. Novartis Found Symp 289:43–52; discussion 53-49, 87-93

    Article  PubMed  Google Scholar 

  • Catts VS, Al-Menhali N, Burne TH, Colditz MJ, Coulson EJ (2008) The p75 neurotrophin receptor regulates hippocampal neurogenesis and related behaviours. Eur J Neurosci 28:883–892

    Article  PubMed  Google Scholar 

  • Chen J, Li CR, Yang H, Liu J, Zhang T, Jiao SS, Wang YJ, Xu ZQ (2016) proBDNF attenuates Hippocampal Neurogenesis and induces learning and memory deficits in aged mice. Neurotox Res 29:47–53

    Article  PubMed  CAS  Google Scholar 

  • Colditz MJ, Catts VS, Al-menhali N, Osborne GW, Bartlett PF, Coulson EJ (2010) p75 neurotrophin receptor regulates basal and fluoxetine-stimulated hippocampal neurogenesis. Exp Brain Res 200:161–167

    Article  PubMed  CAS  Google Scholar 

  • Conover JC, Yancopoulos GD (1997) Neurotrophin regulation of the developing nervous system: analyses of knockout mice. Rev Neurosci 8:13–27

    Article  PubMed  CAS  Google Scholar 

  • Dieni S, Matsumoto T, Dekkers M, Rauskolb S, Ionescu MS, Deogracias R, Gundelfinger ED, Kojima M, Nestel S, Frotscher M, Barde YA (2012) BDNF and its pro-peptide are stored in presynaptic dense core vesicles in brain neurons. J Cell Biol 196:775–788

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ding Q, Ying Z, Gomez-Pinilla F (2011) Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing. Neuroscience 192:773–780

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dokter M, von Bohlen und Halbach O (2012) Neurogenesis within the adult hippocampus under physiological conditions and in depression. Neural Regen Res 7:8

    Google Scholar 

  • Dokter M, Busch R, Poser R, Vogt MA, von Bohlen und Halbach V, Gass P, Unsicker K, von Bohlen und Halbach O (2015) Implications of p75NTR for dentate gyrus morphology and hippocampus-related behavior revisited. Brain Struct Funct 220:1449–1462

    Article  PubMed  CAS  Google Scholar 

  • Dougherty KD, Milner TA (1999) p75NTR immunoreactivity in the rat dentate gyrus is mostly within presynaptic profiles but is also found in some astrocytic and postsynaptic profiles. J Comp Neurol 407:77–91

    Article  PubMed  CAS  Google Scholar 

  • Dranovsky A, Hen R (2006) Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 59:1136–1143

    Article  PubMed  CAS  Google Scholar 

  • Eldomiaty MA, Almasry SM, Desouky MK, Algaidi SA (2017) Voluntary running improves depressive behaviours and the structure of the hippocampus in rats: a possible impact of myokines. Brain Res 1657:29–42

    Article  PubMed  CAS  Google Scholar 

  • Engert F, Bonhoeffer T (1999) Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399:66–70

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ernfors P, Lee KF, Jaenisch R (1994) Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368:147–150

    Article  PubMed  CAS  Google Scholar 

  • Fabel K, Wolf SA, Ehninger D, Babu H, Leal-Galicia P, Kempermann G (2009) Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice. Front Neurosci 3:50

    PubMed  PubMed Central  Google Scholar 

  • Fiala JC, Feinberg M, Popov V, Harris KM (1998) Synaptogenesis via dendritic filopodia in developing hippocampal area CA1. J Neurosci 18:8900–8911

    Article  PubMed  CAS  Google Scholar 

  • Foltran RB, Diaz SL (2016) BDNF isoforms: a round trip ticket between neurogenesis and serotonin? J Neurochem 138:204–221

    Article  PubMed  CAS  Google Scholar 

  • Frodl T, Schule C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Moller HJ, Meisenzahl EM (2007) Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 64:410–416

    Article  PubMed  CAS  Google Scholar 

  • Fujii T, Kunugi H (2009) p75NTR as a therapeutic target for neuropsychiatric diseases. Curr Mol Pharmacol 2:70–76

    Article  PubMed  CAS  Google Scholar 

  • Gau YT, Liou YJ, Yu YW, Chen TJ, Lin MW, Tsai SJ, Hong CJ (2008) Evidence for association between genetic variants of p75 neurotrophin receptor (p75NTR) gene and antidepressant treatment response in Chinese major depressive disorder. Am J Med Genet B 147B:594–599

    Article  CAS  Google Scholar 

  • Geinisman Y (2000) Structural synaptic modifications associated with hippocampal LTP and behavioral learning. Cereb Cortex 10:952–962

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Pinilla F, So V, Kesslak JP (2001) Spatial learning induces neurotrophin receptor and synapsin I in the hippocampus. Brain Res 904:13–19

    Article  PubMed  CAS  Google Scholar 

  • Goncalves JT, Schafer ST, Gage FH (2016) Adult Neurogenesis in the hippocampus: from stem cells to behavior. Cell 167:897–914

    Article  PubMed  CAS  Google Scholar 

  • Gonul AS, Kitis O, Eker MC, Eker OD, Ozan E, Coburn K (2011) Association of the brain-derived neurotrophic factor Val66Met polymorphism with hippocampus volumes in drug-free depressed patients. World J Biol Psychiatry 12:110–118

    Article  PubMed  Google Scholar 

  • Gosnell SN, Velasquez KM, Molfese DL, Molfese PJ, Madan A, Fowler JC, Christopher Frueh B, Baldwin PR, Salas R (2016) Prefrontal cortex, temporal cortex, and hippocampus volume are affected in suicidal psychiatric patients. Psychiatry Res 256:50–56

    Article  Google Scholar 

  • Guo J, Wang J, Zhang Z, Yan J, Chen M, Pang T, Zhang L, Liao H (2013) proNGF inhibits Neurogenesis and induces Glial activation in adult mouse dentate Gyrus. Neurochem Res 38:1695–1703

    Article  PubMed  CAS  Google Scholar 

  • Guo J, Ji Y, Ding Y, Jiang W, Sun Y, Lu B, Nagappan G (2016) BDNF pro-peptide regulates dendritic spines via caspase-3. Cell Death Dis 7:e2264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gustafson D, Lissner L, Bengtsson C, Bjorkelund C, Skoog I (2004) A 24-year follow-up of body mass index and cerebral atrophy. Neurology 63:1876–1881

    Article  PubMed  CAS  Google Scholar 

  • Hall J, Thomas KL, Everitt BJ (2000) Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci 3:533–535

    Article  PubMed  CAS  Google Scholar 

  • Harris KM, Jensen FE, Tsao B (1992) Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosci 12:2685–2705

    Article  PubMed  CAS  Google Scholar 

  • Harrisberger F, Smieskova R, Schmidt A, Lenz C, Walter A, Wittfeld K, Grabe HJ, Lang UE, Fusar-Poli P, Borgwardt S (2015) BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: a systematic review and meta-analysis. Neurosci Biobehav Rev 55:107–118

    Article  PubMed  CAS  Google Scholar 

  • Harward SC, Hedrick NG, Hall CE, Parra-Bueno P, Milner TA, Pan E, Laviv T, Hempstead BL, Yasuda R, McNamara JO (2016) Autocrine BDNF-TrkB signalling within a single dendritic spine. Nature 538:99–103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hasegawa S, Sakuragi S, Tominaga-Yoshino K, Ogura A (2015) Dendritic spine dynamics leading to spine elimination after repeated inductions of LTD. Sci Rep 5:7707

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hasselmo ME, McClelland JL (1999) Neural models of memory. Curr Opin Neurobiol 9:184–188

    Article  PubMed  CAS  Google Scholar 

  • Hercher C, Canetti L, Turecki G, Mechawar N (2010) Anterior cingulate pyramidal neurons display altered dendritic branching in depressed suicides. J Psychiatr Res 44:286–293

    Article  PubMed  Google Scholar 

  • Hong KW, Lim JE, Go MJ, Shin Cho Y, Ahn Y, Han BG, Oh B (2012) Recapitulation of the association of the Val66Met polymorphism of BDNF gene with BMI in Koreans. Obesity (Silver Spring) 20:1871–1875

    Article  CAS  Google Scholar 

  • Horch HW, Katz LC (2002) BDNF release from single cells elicits local dendritic growth in nearby neurons. Nat Neurosci 5:1177–1184

    Article  PubMed  CAS  Google Scholar 

  • Ikegaya Y, Ishizaka Y, Matsuki N (2002) BDNF attenuates hippocampal LTD via activation of phospholipase C: implications for a vertical shift in the frequency-response curve of synaptic plasticity. Eur J Neurosci 16:145–148

    Article  PubMed  Google Scholar 

  • Ivanova T, Beyer C (2001) Pre- and postnatal expression of brain-derived neurotrophic factor mRNA/protein and tyrosine protein kinase receptor B mRNA in the mouse hippocampus. Neurosci Lett 307:21–24

    Article  PubMed  CAS  Google Scholar 

  • Jessen F, Schuhmacher A, von Widdern O, Guttenthaler V, Hofels S, Suliman H, Scheef L, Block W, Urbach H, Maier W, Zobel A (2009) No association of the Val66Met polymorphism of the brain-derived neurotrophic factor with hippocampal volume in major depression. Psychiatr Genet 19:99–101

    Article  PubMed  Google Scholar 

  • Joffe RT, Gatt JM, Kemp AH, Grieve S, Dobson-Stone C, Kuan SA, Schofield PR, Gordon E, Williams LM (2009) Brain derived neurotrophic factor Val66Met polymorphism, the five factor model of personality and hippocampal volume: implications for depressive illness. Hum Brain Mapp 30:1246–1256

    Article  PubMed  Google Scholar 

  • Karege F, Vaudan G, Schwald M, Perroud N, La Harpe R (2005) Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 136:29–37

    Article  PubMed  CAS  Google Scholar 

  • Katoh-Semba R, Takeuchi IK, Semba R, Kato K (1997) Distribution of brain-derived neurotrophic factor in rats and its changes with development in the brain. J Neurochem 69:34–42

    Article  PubMed  CAS  Google Scholar 

  • Ke Z, Yip SP, Li L, Zheng XX, Tong KY (2011) The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: a rat brain ischemia model. PLoS ONE 6:e16643

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kempermann G, Kronenberg G (2003) Depressed new neurons--adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biol Psychiatry 54:499–503

    Article  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  PubMed  CAS  Google Scholar 

  • Kernie SG, Liebl DJ, Parada LF (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19:1290–1300

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim YK, Lee HP, Won SD, Park EY, Lee HY, Lee BH, Lee SW, Yoon D, Han C, Kim DJ, Choi SH (2007) Low plasma BDNF is associated with suicidal behavior in major depression. Prog Neuro-Psychopharmacol Biol Psychiatry 31:78–85

    Article  CAS  Google Scholar 

  • Klein R, Smeyne RJ, Wurst W, Long LK, Auerbach BA, Joyner AL, Barbacid M (1993) Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 75:113–122

    Article  PubMed  CAS  Google Scholar 

  • Kolbeck R, Jungbluth S, Barde YA (1994) Characterisation of neurotrophin dimers and monomers. Eur J Biochem 225:995–1003

    Article  PubMed  CAS  Google Scholar 

  • Konur S, Rabinowitz D, Fenstermaker VL, Yuste R (2003) Systematic regulation of spine sizes and densities in pyramidal neurons. J Neurobiol 56:95–112

    Article  PubMed  Google Scholar 

  • Kunugi H, Hashimoto R, Yoshida M, Tatsumi M, Kamijima K (2004) A missense polymorphism (S205L) of the low-affinity neurotrophin receptor p75NTR gene is associated with depressive disorder and attempted suicide. Am J Med Genet B 129B:44–46

    Article  Google Scholar 

  • Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ (2004) Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. Am J Psychiatry 161:1848–1855

    Article  PubMed  Google Scholar 

  • Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV, Jaenisch R (1992) Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69:737–749

    Article  PubMed  CAS  Google Scholar 

  • Lee TH, Kato H, Pan LH, Ryu JH, Kogure K, Itoyama Y (1998) Localization of nerve growth factor, trkA and P75 immunoreactivity in the hippocampal formation and basal forebrain of adult rats. Neuroscience 83:335–349

    Article  PubMed  CAS  Google Scholar 

  • Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948

    Article  PubMed  CAS  Google Scholar 

  • Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375

    Article  PubMed  CAS  Google Scholar 

  • Leuner B, Shors TJ (2004) New spines, new memories. Mol Neurobiol 29:117–130

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Leuner B, Falduto J, Shors TJ (2003) Associative memory formation increases the observation of dendritic spines in the hippocampus. J Neurosci 23:659–665

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li G, Jing P, Liu Z, Li Z, Ma H, Tu W, Zhang W, Zhuo C (2017) Beneficial effect of fluoxetine treatment against psychological stress is mediated by increasing BDNF expression in selected brain areas. Oncotarget 8:69527–69537

    PubMed  PubMed Central  Google Scholar 

  • Liao GY, Li Y, Xu B (2013) Ablation of TrkB expression in RGS9-2 cells leads to hyperphagic obesity. Mol Metab 2:491–497

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lømo T (2018) Discovering long-term potentiation (LTP) - recollections and reflections on what came after. Acta Physiol (Oxf) 222(2). https://doi.org/10.1111/apha.12921

  • Maclean CJ, Baker HF, Fine A, Ridley RM (1997) The distribution of p75 neurotrophin receptor-immunoreactive cells in the forebrain of the common marmoset (Callithrix Jacchus). Brain Res Bull 43:197–208

    Article  PubMed  CAS  Google Scholar 

  • Magarinos AM, Li CJ, Gal Toth J, Bath KG, Jing D, Lee FS, McEwen BS (2011) Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus 21:253–264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Malenka RC, Nicoll RA (1999) Long-term potentiation--a decade of progress? Science 285:1870–1874

    Article  PubMed  CAS  Google Scholar 

  • Marlatt MW, Potter MC, Lucassen PJ, van Praag H (2012) Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Dev Neurobiol 72:943–952

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Martin AA, Davidson TL (2014) Human cognitive function and the obesogenic environment. Physiol Behav 136:185–189

    Article  PubMed  CAS  Google Scholar 

  • Martinowich K, Manji H, Lu B (2007) New insights into BDNF function in depression and anxiety. Nat Neurosci 10:1089–1093

    Article  PubMed  CAS  Google Scholar 

  • Martinowich K, Schloesser RJ, Lu Y, Jimenez DV, Paredes D, Greene JS, Greig NH, Manji HK, Lu B (2012) Roles of p75(NTR), long-term depression, and cholinergic transmission in anxiety and acute stress coping. Biol Psychiatry 71:75–83

    Article  PubMed  CAS  Google Scholar 

  • Maynard KR, Hobbs JW, Sukumar M, Kardian AS, Jimenez DV, Schloesser RJ, Martinowich K (2017) Bdnf mRNA splice variants differentially impact CA1 and CA3 dendrite complexity and spine morphology in the hippocampus. Brain Struct Funct 222(7):3295–3307. https://doi.org/10.1007/s00429-017-1405-3

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Medina DL, Sciarretta C, Calella AM, von Bohlen und Halbach O, Unsicker K, Minichiello L (2004) TrkB regulates neocortex formation through the Shc/PLCgamma-mediated control of neuronal migration. EMBO J 23:3803–3814

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Megias M, Emri Z, Freund TF, Gulyas AI (2001) Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells. Neuroscience 102:527–540

    Article  PubMed  CAS  Google Scholar 

  • Mervaala E, Fohr J, Kononen M, Valkonen-Korhonen M, Vainio P, Partanen K, Partanen J, Tiihonen J, Viinamaki H, Karjalainen AK, Lehtonen J (2000) Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med 30:117–125

    Article  PubMed  CAS  Google Scholar 

  • Minichiello L (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 10:850–860

    Article  PubMed  CAS  Google Scholar 

  • Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V, Rossi-Arnaud C, Lipp HP, Bonhoeffer T, Klein R (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24:401–414

    Article  PubMed  CAS  Google Scholar 

  • Mizui T, Ishikawa Y, Kumanogoh H, Lume M, Matsumoto T, Hara T, Yamawaki S, Takahashi M, Shiosaka S, Itami C, Uegaki K, Saarma M, Kojima M (2015) BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met. Proc Natl Acad Sci U S A 112:E3067–E3074

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Mizui T, Ohira K, Kojima M (2017) BDNF pro-peptide: a novel synaptic modulator generated as an N-terminal fragment from the BDNF precursor by proteolytic processing. Neural Regen Res 12:1024–1027

    Article  PubMed  PubMed Central  Google Scholar 

  • Mizuseki K, Miyawaki H (2017) Hippocampal information processing across sleep/wake cycles. Neurosci Res 118:30–47

    Article  PubMed  Google Scholar 

  • Monfils MH, Teskey GC (2004) Induction of long-term depression is associated with decreased dendritic length and spine density in layers III and V of sensorimotor neocortex. Synapse 53:114–121

    Article  PubMed  CAS  Google Scholar 

  • Monteggia LM, Luikart B, Barrot M, Theobold D, Malkovska I, Nef S, Parada LF, Nestler EJ (2007) Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol Psychiatry 61:187–197

    Article  PubMed  CAS  Google Scholar 

  • Moser MB, Trommald M, Andersen P (1994) An increase in dendritic spine density on hippocampal CA1 pyramidal cells following spatial learning in adult rats suggests the formation of new synapses. Proc Natl Acad Sci U S A 91:12673–12675

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Muller D, Toni N, Buchs PA (2000) Spine changes associated with long-term potentiation. Hippocampus 10:596–604

    Article  PubMed  CAS  Google Scholar 

  • Muller MB, Lucassen PJ, Yassouridis A, Hoogendijk WJ, Holsboer F, Swaab DF (2001) Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus. Eur J Neurosci 14:1603–1612

    Article  PubMed  CAS  Google Scholar 

  • Naber PA, Witter MP, Lopes Silva FH (2000) Networks of the hippocampal memory system of the rat. The pivotal role of the subiculum. Ann N Y Acad Sci 911:392–403

    Article  PubMed  CAS  Google Scholar 

  • Nimchinsky EA, Sabatini BL, Svoboda K (2002) Structure and function of dendritic spines. Annu Rev Physiol 64:313–353

    Article  PubMed  CAS  Google Scholar 

  • Norrholm SD, Ouimet CC (2001) Altered dendritic spine density in animal models of depression and in response to antidepressant treatment. Synapse 42:151–163

    Article  PubMed  CAS  Google Scholar 

  • Nykjaer A, Willnow TE (2012) Sortilin: a receptor to regulate neuronal viability and function. Trends Neurosci 35:261–270

    Article  PubMed  CAS  Google Scholar 

  • Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM (2004) Sortilin is essential for proNGF-induced neuronal cell death. Nature 427:843–848

    Article  PubMed  CAS  Google Scholar 

  • O’Malley A, O’Connell C, Murphy KJ, Regan CM (2000) Transient spine density increases in the mid-molecular layer of hippocampal dentate gyrus accompany consolidation of a spatial learning task in the rodent. Neuroscience 99:229–232

    Article  PubMed  Google Scholar 

  • Park HR, Park M, Choi J, Park KY, Chung HY, Lee J (2010) A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett 482:235–239

    Article  PubMed  CAS  Google Scholar 

  • Parnass Z, Tashiro A, Yuste R (2000) Analysis of spine morphological plasticity in developing hippocampal pyramidal neurons. Hippocampus 10:561–568

    Article  PubMed  CAS  Google Scholar 

  • Paul CE, Vereker E, Dickson KM, Barker PA (2004) A pro-apoptotic fragment of the p75 neurotrophin receptor is expressed in p75NTRExonIV null mice. J Neurosci 24:1917–1923

    Article  PubMed  CAS  Google Scholar 

  • Petzold A, Psotta L, Brigadski T, Endres T, Lessmann V (2015) Chronic BDNF deficiency leads to an age-dependent impairment in spatial learning. Neurobiol Learn Mem 120:52–60

    Article  PubMed  CAS  Google Scholar 

  • Pinar C, Fontaine CJ, Trivino-Paredes J, Lottenberg CP, Gil-Mohapel J, Christie BR (2017) Revisiting the flip side: long-term depression of synaptic efficacy in the hippocampus. Neurosci Biobehav Rev 80:394–413

    Article  PubMed  Google Scholar 

  • Poser R, Dokter M, von Bohlen und Halbach V, Berger SM, Busch R, Baldus M, Unsicker K, von Bohlen und Halbach O (2015) Impact of a deletion of the full-length and short isoform of p75NTR on cholinergic innervation and the population of postmitotic doublecortin positive cells in the dentate gyrus. Front Neuroanat 9:63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Qiao H, An SC, Ren W, Ma XM (2014) Progressive alterations of hippocampal CA3-CA1 synapses in an animal model of depression. Behav Brain Res 275:191–200

    Article  PubMed  Google Scholar 

  • Qiao H, An SC, Xu C, Ma XM (2017) Role of proBDNF and BDNF in dendritic spine plasticity and depressive-like behaviors induced by an animal model of depression. Brain Res 1663:29–37

    Article  PubMed  CAS  Google Scholar 

  • Rampon C, Tang YP, Goodhouse J, Shimizu E, Kyin M, Tsien JZ (2000) Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice. Nat Neurosci 3:238–244

    Article  PubMed  CAS  Google Scholar 

  • Rantamaki T, Hendolin P, Kankaanpaa A, Mijatovic J, Piepponen P, Domenici E, Chao MV, Mannisto PT, Castren E (2007) Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology 32:2152–2162

    Article  PubMed  CAS  Google Scholar 

  • Renelt M, von Bohlen und Halbach V, von Bohlen und Halbach O (2014) Distribution of PCP4 protein in the forebrain of adult mice. Acta Histochem 116:1056–1061

    Article  PubMed  CAS  Google Scholar 

  • Reymann KG, Frey JU (2007) The late maintenance of hippocampal LTP: requirements, phases, ‘synaptic tagging’, ‘late-associativity’ and implications. Neuropharmacology 52:24–40

    Article  PubMed  CAS  Google Scholar 

  • Rolls ET (2000) Memory systems in the brain. Annu Rev Psychol 51:599–630

    Article  PubMed  CAS  Google Scholar 

  • Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N, Hays AP, Dwork AJ (2000) Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings. Arch Gen Psychiatry 57:349–356

    Article  PubMed  CAS  Google Scholar 

  • Sarret P, Krzywkowski P, Segal L, Nielsen MS, Petersen CM, Mazella J, Stroh T, Beaudet A (2003) Distribution of NTS3 receptor/sortilin mRNA and protein in the rat central nervous system. J Comp Neurol 461:483–505

    Article  PubMed  CAS  Google Scholar 

  • Schmitz C, Rhodes ME, Bludau M, Kaplan S, Ong P, Ueffing I, Vehoff J, Korr H, Frye CA (2002) Depression: reduced number of granule cells in the hippocampus of female, but not male, rats due to prenatal restraint stress. Mol Psychiatry 7:810–813

    Article  PubMed  CAS  Google Scholar 

  • Sharma S, Fulton S (2013) Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry. Int J Obes 37:382–389

    Article  CAS  Google Scholar 

  • Sheldrick A, Camara S, Ilieva M, Riederer P, Michel TM (2017) Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) levels in post-mortem brain tissue from patients with depression compared to healthy individuals - a proof of concept study. Eur Psychiatry 46:65–71

    Article  PubMed  CAS  Google Scholar 

  • Sheng M, Erturk A (2014) Long-term depression: a cell biological view. Philos Trans R Soc Lond B 369:20130138

    Article  CAS  Google Scholar 

  • Skledar M, Nikolac M, Dodig-Curkovic K, Curkovic M, Borovecki F, Pivac N (2012) Association between brain-derived neurotrophic factor Val66Met and obesity in children and adolescents. Prog Neuro-Psychopharmacol Biol Psychiatry 36:136–140

    Article  CAS  Google Scholar 

  • Sølvsten CA, de Paoli F, Christensen JH, Nielsen AL (2016) Voluntary physical exercise induces expression and epigenetic remodeling of VegfA in the rat hippocampus. Mol Neurobiol. https://doi.org/10.1007/s12035-016-0344-y

  • Squire LR, Zola SM (1996) Structure and function of declarative and nondeclarative memory systems. Proc Natl Acad Sci U S A 93:13515–13522

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Squire LR, Genzel L, Wixted JT, Morris RG (2015) Memory consolidation. Cold Spring Harb Perspect Biol 7:a021766

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stranahan AM, Lee K, Martin B, Maudsley S, Golden E, Cutler RG, Mattson MP (2009) Voluntary exercise and caloric restriction enhance hippocampal dendritic spine density and BDNF levels in diabetic mice. Hippocampus 19:951–961

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, Kermani P, Torkin R, Chen ZY, Lee FS, Kraemer RT, Nykjaer A, Hempstead BL (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25:5455–5463

    Article  PubMed  CAS  Google Scholar 

  • Teng KK, Felice S, Kim T, Hempstead BL (2010) Understanding proneurotrophin actions: recent advances and challenges. Dev Neurobiol 70:350–359

    PubMed  PubMed Central  CAS  Google Scholar 

  • Toni N, Buchs PA, Nikonenko I, Bron CR, Muller D (1999) LTP promotes formation of multiple spine synapses between a single axon terminal and a dendrite. Nature 402:421–425

    Article  PubMed  CAS  Google Scholar 

  • Tozuka Y, Wada E, Wada K (2009) Diet-induced obesity in female mice leads to peroxidized lipid accumulations and impairment of hippocampal neurogenesis during the early life of their offspring. FASEB J 23:1920–1934

    Article  PubMed  CAS  Google Scholar 

  • Vaegter CB, Jansen P, Fjorback AW, Glerup S, Skeldal S, Kjolby M, Richner M, Erdmann B, Nyengaard JR, Tessarollo L, Lewin GR, Willnow TE, Chao MV, Nykjaer A (2011) Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling. Nat Neurosci 14:54–61

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:2580–2590

    Article  PubMed  Google Scholar 

  • Veena J, Rao BS, Srikumar BN (2011) Regulation of adult neurogenesis in the hippocampus by stress, acetylcholine and dopamine. J Nat Sci Biol Med 2:26–37

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • von Bohlen und Halbach O (2010a) Dendritic spine abnormalities in mental retardation. Cell Tissue Res 342:317–323

    Article  Google Scholar 

  • von Bohlen und Halbach O (2010b) Involvement of BDNF in age-dependent alterations in the hippocampus. Front Aging Neurosci 2:36

    Google Scholar 

  • von Bohlen und Halbach O, Minichiello L, Unsicker K (2003) Haploinsufficiency in trkB and/or trkC neurotrophin receptors causes structural alterations in the aged hippocampus and amygdala. Eur J Neurosci 18:2319–2325

    Article  Google Scholar 

  • von Bohlen und Halbach O, Krause S, Medina D, Sciarretta C, Minichiello L, Unsicker K (2006a) Regional- and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies. Biol Psychiatry 59:793–800

    Article  CAS  Google Scholar 

  • von Bohlen und Halbach O, Zacher C, Gass P, Unsicker K (2006b) Age-related alterations in hippocampal spines and deficiencies in spatial memory in mice. J Neurosci Res 83:525–531

    Article  CAS  Google Scholar 

  • von Bohlen und Halbach O, Minichiello L, Unsicker K (2008) TrkB but not trkC receptors are necessary for postnatal maintenance of hippocampal spines. Neurobiol Aging 29:1247–1255

    Article  CAS  Google Scholar 

  • von Schack D, Casademunt E, Schweigreiter R, Meyer M, Bibel M, Dechant G (2001) Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat Neurosci 4:977–978

    Article  Google Scholar 

  • Voronin L, Byzov A, Kleschevnikov A, Kozhemyakin M, Kuhnt U, Volgushev M (1995) Neurophysiological analysis of long-term potentiation in mammalian brain. Behav Brain Res 66:45–52

    Article  PubMed  CAS  Google Scholar 

  • Webster MJ, Herman MM, Kleinman JE, Shannon Weickert C (2006) BDNF and trkB mRNA expression in the hippocampus and temporal cortex during the human lifespan. Gene Expr Patterns 6:941–951

    Article  PubMed  CAS  Google Scholar 

  • Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science 313:1093–1097

    Article  PubMed  CAS  Google Scholar 

  • Willette AA, Kapogiannis D (2015) Does the brain shrink as the waist expands? Ageing Res Rev 20:86–97

    Article  PubMed  Google Scholar 

  • Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8:1069–1077

    Article  PubMed  CAS  Google Scholar 

  • Xenos D, Kamceva M, Tomasi S, Cardin JA, Schwartz ML, Vaccarino FM (2017) Loss of TrkB Signaling in Parvalbumin-expressing basket cells results in network activity disruption and abnormal behavior. Cereb Cortex:1–15

  • Xia J, Chen J, Zhou Y, Zhang J, Yang B, Xia L, Wang C (2004) Volumetric MRI analysis of the amygdala and hippocampus in subjects with major depression. J Huazhong Univ Sci Technol Med Sci 24(500–502):506

    Google Scholar 

  • Yamada N, Katsuura G, Ochi Y, Ebihara K, Kusakabe T, Hosoda K, Nakao K (2011) Impaired CNS leptin action is implicated in depression associated with obesity. Endocrinology 152:2634–2643

    Article  PubMed  CAS  Google Scholar 

  • Yan Q, Radeke MJ, Matheson CR, Talvenheimo J, Welcher AA, Feinstein SC (1997) Immunocytochemical localization of TrkB in the central nervous system of the adult rat. J Comp Neurol 378:135–157

    Article  PubMed  CAS  Google Scholar 

  • Yang J, Harte-Hargrove LC, Siao CJ, Marinic T, Clarke R, Ma Q, Jing D, Lafrancois JJ, Bath KG, Mark W, Ballon D, Lee FS, Scharfman HE, Hempstead BL (2014) proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep 7:796–806

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yeo TT, Chua-Couzens J, Butcher LL, Bredesen DE, Cooper JD, Valletta JS, Mobley WC, Longo FM (1997) Absence of p75NTR causes increased basal forebrain cholinergic neuron size, choline acetyltransferase activity, and target innervation. J Neurosci 17:7594–7605

    Article  PubMed  CAS  Google Scholar 

  • Yuste R, Bonhoeffer T (2001) Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu Rev Neurosci 24:1071–1089

    Article  PubMed  CAS  Google Scholar 

  • Zagrebelsky M, Holz A, Dechant G, Barde YA, Bonhoeffer T, Korte M (2005) The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. J Neurosci 25:9989–9999

    Article  PubMed  CAS  Google Scholar 

  • Zeng J, Racicott J, Morales CR (2009) The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes. Exp Cell Res 315:3112–3124

    Article  PubMed  CAS  Google Scholar 

  • Zheng K, An JJ, Yang F, Xu W, Xu ZQ, Wu J, Hokfelt TG, Fisahn A, Xu B, Lu B (2011) TrkB signaling in parvalbumin-positive interneurons is critical for gamma-band network synchronization in hippocampus. Proc Natl Acad Sci U S A 108:17201–17206

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou Q, Homma KJ, Poo MM (2004) Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses. Neuron 44:749–757

    Article  PubMed  CAS  Google Scholar 

  • Zhou L, Xiong J, Lim Y, Ruan Y, Huang C, Zhu Y, Zhong JH, Xiao Z, Zhou XF (2013) Upregulation of blood proBDNF and its receptors in major depression. J Affect Disord 150:776–784

    Article  PubMed  CAS  Google Scholar 

  • Zhou C, Zhong J, Zou B, Fang L, Chen J, Deng X, Zhang L, Zhao X, Qu Z, Lei Y, Lei T (2017) Meta-analyses of comparative efficacy of antidepressant medications on peripheral BDNF concentration in patients with depression. PLoS ONE 12:e0172270

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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  1. Institut für Anatomie und Zellbiologie, Universitätsmedizin Greifswald, Friedrich-Loeffler-Str. 23c, 17487, Greifswald, Germany

    Oliver von Bohlen und Halbach & Viola von Bohlen und Halbach

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von Bohlen und Halbach, O., von Bohlen und Halbach, V. BDNF effects on dendritic spine morphology and hippocampal function. Cell Tissue Res 373, 729–741 (2018). https://doi.org/10.1007/s00441-017-2782-x

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