The role of neurotrophins in major depressive disorder

[1] Lewin G.R., Barde Y.A., Physiology of the neurotrophins, Annu. Rev. Neurosci., 1996, 19, 289–317 http://dx.doi.org/10.1146/annurev.ne.19.030196.00144510.1146/annurev.ne.19.030196.001445Search in Google Scholar

[2] Huang E.J., Reichardt L.F., Neurotrophins: roles in neuronal development and function, Annu. Rev. Neurosci., 2001, 24, 677–736 http://dx.doi.org/10.1146/annurev.neuro.24.1.67710.1146/annurev.neuro.24.1.677Search in Google Scholar

[3] Bibel M., Barde Y.A., Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system, Genes Dev., 2000, 14, 2919–2937 http://dx.doi.org/10.1101/gad.84140010.1101/gad.841400Search in Google Scholar

[4] Levi-Montalcini R., The nerve growth factor: thirty-five years later, Biosci. Rep., 1987, 7, 681–699 http://dx.doi.org/10.1007/BF0111686110.1007/BF01116861Search in Google Scholar

[5] Barde Y.A., Edgar D., Thoenen H., Purification of a new neurotrophic factor from mammalian brain, EMBO J., 1982, 1, 549–553 10.1002/j.1460-2075.1982.tb01207.xSearch in Google Scholar

[6] Maisonpierre P.C., Belluscio L., Squinto S., Ip N.Y., Furth M.E., Lindsay R.M., et al., Neurotrophin-3: a neurotrophic factor related to NGF and BDNF, Science, 1990, 247, 1446–1451 http://dx.doi.org/10.1126/science.232100610.1126/science.2321006Search in Google Scholar

[7] Ip N.Y., Ibanez C.F., Nye S.H., McClain J., Jones P.F., Gies D.R., et al., Mammalian neurotrophin-4: structure, chromosomal localization, tissue distribution, and receptor specificity, Proc. Natl. Acad. Sci. USA, 1992, 89, 3060–3064 http://dx.doi.org/10.1073/pnas.89.7.306010.1073/pnas.89.7.3060Search in Google Scholar

[8] Barbacid M., Neurotrophic factors and their receptors, Curr. Opin. Cell Biol., 1995, 7, 148–155 http://dx.doi.org/10.1016/0955-0674(95)80022-010.1016/0955-0674(95)80022-0Search in Google Scholar

[9] Teng H.K., Teng K.K., Lee R., Wright S., Tevar S., Almeida R.D., et al., ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin, J. Neurosci., 2005, 25, 5455–5463 http://dx.doi.org/10.1523/JNEUROSCI.5123-04.200510.1523/JNEUROSCI.5123-04.2005Search in Google Scholar PubMed PubMed Central

[10] Woo N.H., Teng H.K., Siao C.J., Chiaruttini C., Pang P.T., Milner T.A., et al., Activation of p75NTR by proBDNF facilitates hippocampal longterm depression, Nat. Neurosci., 2005, 8, 1069–1077 http://dx.doi.org/10.1038/nn151010.1038/nn1510Search in Google Scholar PubMed

[11] Zagrebelsky M., Holz A., Dechant G., Barde Y.A., Bonhoeffer T., Korte M., The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons, J. Neurosci., 2005, 25, 9989–9999 http://dx.doi.org/10.1523/JNEUROSCI.2492-05.200510.1523/JNEUROSCI.2492-05.2005Search in Google Scholar

[12] Reichardt L.F., Neurotrophin-regulated signalling pathways, Philos. T. Roy. Soc. B, 2006, 361, 1545–1564 http://dx.doi.org/10.1098/rstb.2006.189410.1098/rstb.2006.1894Search in Google Scholar

[13] Autry A.E., Monteggia L.M., Brain-derived neurotrophic factor and neuropsychiatric disorders, Pharmacol. Rev., 2012, 64, 238–258 http://dx.doi.org/10.1124/pr.111.00510810.1124/pr.111.005108Search in Google Scholar

[14] Nibuya M., Morinobu S., Duman R.S., Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments, J. Neurosci., 1995, 15, 7539–7547 10.1523/JNEUROSCI.15-11-07539.1995Search in Google Scholar

[15] Dwivedi Y., Rizavi H.S., Conley R.R., Roberts R.C., Tamminga C.A., Pandey G.N., Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects, Arch. Gen. Psychiat., 2003, 60, 804–815 http://dx.doi.org/10.1001/archpsyc.60.8.80410.1001/archpsyc.60.8.804Search in Google Scholar

[16] Karege F., Vaudan G., Schwald M., Perroud N., La Harpe R., Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs, Mol. Brain Res., 2005, 136, 29–37 http://dx.doi.org/10.1016/j.molbrainres.2004.12.02010.1016/j.molbrainres.2004.12.020Search in Google Scholar

[17] Guilloux J.P., Douillard-Guilloux G., Kota R., Wang X., Gardier A.M., Martinowich K., et al., Molecular evidence for BDNF- and GABArelated dysfunctions in the amygdala of female subjects with major depression, Mol. Psychiatr., 2012, 17, 1130–1142 http://dx.doi.org/10.1038/mp.2011.11310.1038/mp.2011.113Search in Google Scholar

[18] Chen B., Dowlatshahi D., MacQueen G.M., Wang J.F., Young L.T., Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication, Biol. Psychiat., 2001, 50, 260–265 http://dx.doi.org/10.1016/S0006-3223(01)01083-610.1016/S0006-3223(01)01083-6Search in Google Scholar

[19] Karege F., Perret G., Bondolfi G., Schwald M., Bertschy G., Aubry J.M., Decreased serum brain-derived neurotrophic factor levels in major depressed patients, Psychiat. Res., 2002, 109, 143–148 http://dx.doi.org/10.1016/S0165-1781(02)00005-710.1016/S0165-1781(02)00005-7Search in Google Scholar

[20] Yoshida T., Ishikawa M., Niitsu T., Nakazato M., Watanabe H., Shiraishi T., et al., Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder, PLoS One, 2012, 7, e42676 http://dx.doi.org/10.1371/journal.pone.004267610.1371/journal.pone.0042676Search in Google Scholar PubMed PubMed Central

[21] Lee B.H., Kim H., Park S.H., Kim Y.K., Decreased plasma BDNF level in depressive patients, J. Affect. Disord., 2007, 101, 239–244 http://dx.doi.org/10.1016/j.jad.2006.11.00510.1016/j.jad.2006.11.005Search in Google Scholar

[22] Karege F., Bondolfi G., Gervasoni N., Schwald M., Aubry J.M., Bertschy G., Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity, Biol. Psychiat., 2005, 57, 1068–1072 http://dx.doi.org/10.1016/j.biopsych.2005.01.00810.1016/j.biopsych.2005.01.008Search in Google Scholar

[23] Shimizu E., Hashimoto K., Okamura N., Koike K., Komatsu N., Kumakiri C., et al., Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants, Biol. Psychiat., 2003, 54, 70–75 http://dx.doi.org/10.1016/S0006-3223(03)00181-110.1016/S0006-3223(03)00181-1Search in Google Scholar

[24] Deuschle M., Gilles M., Scharnholz B., Lederbogen F., Lang U.E., Hellweg R., Changes of serum concentrations of brain-derived neurotrophic factor (BDNF) during treatment with venlafaxine and mirtazapine: role of medication and response to treatment, Pharmacopsychiatry, 2012, Epub ahead of print, doi: 10.1055/s-0032-1321908 10.1055/s-0032-1321908Search in Google Scholar PubMed

[25] Lee H.Y., Kim Y.K., Plasma brain-derived neurotrophic factor as a peripheral marker for the action mechanism of antidepressants, Neuropsychobiology, 2008, 57, 194–199 http://dx.doi.org/10.1159/00014981710.1159/000149817Search in Google Scholar PubMed

[26] Lee B.H., Kim Y.K., Reduced platelet BDNF level in patients with major depression, Prog. Neuropsychopharmacol. Biol. Psychiat., 2009, 33, 849–853 http://dx.doi.org/10.1016/j.pnpbp.2009.04.00210.1016/j.pnpbp.2009.04.002Search in Google Scholar PubMed

[27] Lee B.H., Kim Y.K., BDNF mRNA expression of peripheral blood mononuclear cells was decreased in depressive patients who had or had not recently attempted suicide, J. Affect. Disord., 2010, 125, 369–373 http://dx.doi.org/10.1016/j.jad.2010.01.07410.1016/j.jad.2010.01.074Search in Google Scholar PubMed

[28] Pandey G.N., Dwivedi Y., Rizavi H.S., Ren X., Zhang H., Pavuluri M.N., Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2010, 34, 645–651 http://dx.doi.org/10.1016/j.pnpbp.2010.03.00310.1016/j.pnpbp.2010.03.003Search in Google Scholar PubMed

[29] Kim Y.K., Lee H.P., Won S.D., Park E.Y., Lee H.Y., Lee B.H., et al., Low plasma BDNF is associated with suicidal behavior in major depression, Prog. Neuropsychopharmacol. Biol. Psychiat., 2007, 31, 78–85 http://dx.doi.org/10.1016/j.pnpbp.2006.06.02410.1016/j.pnpbp.2006.06.024Search in Google Scholar PubMed

[30] Birkenhager T.K., Geldermans S., Van den Broek W.W., van Beveren N., Fekkes D., Serum brain-derived neurotrophic factor level in relation to illness severity and episode duration in patients with major depression, J. Psychiat. Res., 2012, 46, 285–289 http://dx.doi.org/10.1016/j.jpsychires.2011.12.00610.1016/j.jpsychires.2011.12.006Search in Google Scholar PubMed

[31] Lang U.E., Hellweg R., Gallinat J., BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits, Neuropsychopharmacology, 2004, 29, 795–798 http://dx.doi.org/10.1038/sj.npp.130038210.1038/sj.npp.1300382Search in Google Scholar

[32] Klein A.B., Williamson R., Santini M.A., Clemmensen C., Ettrup A., Rios M., et al., Blood BDNF concentrations reflect brain-tissue BDNF levels across species, Int. J. Neuropsychopharmacol., 2011, 14, 347–353 http://dx.doi.org/10.1017/S146114571000073810.1017/S1461145710000738Search in Google Scholar

[33] Smith M.A., Makino S., Kvetnansky R., Post R.M., Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus, J. Neurosci., 1995, 15, 1768–1777 10.1523/JNEUROSCI.15-03-01768.1995Search in Google Scholar

[34] Ueyama T., Kawai Y., Nemoto K., Sekimoto M., Tone S., Senba E., Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain, Neurosci. Res., 1997, 28, 103–110 http://dx.doi.org/10.1016/S0168-0102(97)00030-810.1016/S0168-0102(97)00030-8Search in Google Scholar

[35] Rasmusson A.M., Shi L., Duman R., Downregulation of BDNF mRNA in the hippocampal dentate gyrus after re-exposure to cues previously associated with footshock, Neuropsychopharmacology, 2002, 27, 133–142 http://dx.doi.org/10.1016/S0893-133X(02)00286-510.1016/S0893-133X(02)00286-5Search in Google Scholar

[36] Luo C., Xu H., Li X.M., Post-stress changes in BDNF and Bcl-2 immunoreactivities in hippocampal neurons: effect of chronic administration of olanzapine, Brain Res., 2004, 1025, 194–202 http://dx.doi.org/10.1016/j.brainres.2004.06.08910.1016/j.brainres.2004.06.089Search in Google Scholar PubMed

[37] Pizarro J.M., Lumley L.A., Medina W., Robison C.L., Chang W.E., Alagappan A., et al., Acute social defeat reduces neurotrophin expression in brain cortical and subcortical areas in mice, Brain Res., 2004, 1025, 10–20 http://dx.doi.org/10.1016/j.brainres.2004.06.08510.1016/j.brainres.2004.06.085Search in Google Scholar PubMed

[38] Berry A., Bellisario V., Capoccia S., Tirassa P., Calza A., Alleva E., et al., Social deprivation stress is a triggering factor for the emergence of anxiety- and depression-like behaviours and leads to reduced brain BDNF levels in C57BL/6J mice, Psychoneuroendocrinology, 2012, 37, 762–772 http://dx.doi.org/10.1016/j.psyneuen.2011.09.00710.1016/j.psyneuen.2011.09.007Search in Google Scholar PubMed

[39] Gronli J., Bramham C., Murison R., Kanhema T., Fiske E., Bjorvatn B., et al., Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper, Pharmacol. Biochem. Behav., 2006, 85, 842–849 http://dx.doi.org/10.1016/j.pbb.2006.11.02110.1016/j.pbb.2006.11.021Search in Google Scholar PubMed

[40] Tsankova N.M., Berton O., Renthal W., Kumar A., Neve R.L., Nestler E.J., Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action, Nat. Neurosci., 2006, 9, 519–525 http://dx.doi.org/10.1038/nn165910.1038/nn1659Search in Google Scholar PubMed

[41] Allaman I., Papp M., Kraftsik R., Fiumelli H., Magistretti P.J., Martin J.L., Expression of brain-derived neurotrophic factor is not modulated by chronic mild stress in the rat hippocampus and amygdala, Pharmacol. Rep., 2008, 60, 1001–1007 Search in Google Scholar

[42] Lucca G., Comim C.M., Valvassori S.S., Pereira J.G., Stertz L., Gavioli E.C., et al., Chronic mild stress paradigm reduces sweet food intake in rats without affecting brain derived neurotrophic factor protein levels, Curr. Neurovasc. Res., 2008, 5, 207–213 http://dx.doi.org/10.2174/15672020878641340610.2174/156720208786413406Search in Google Scholar PubMed

[43] Marmigere F., Givalois L., Rage F., Arancibia S., Tapia-Arancibia L., Rapid induction of BDNF expression in the hippocampus during immobilization stress challenge in adult rats, Hippocampus, 2003, 13, 646–655 http://dx.doi.org/10.1002/hipo.1010910.1002/hipo.10109Search in Google Scholar PubMed

[44] Larsen M.H., Mikkelsen J.D., Hay-Schmidt A., Sandi C., Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment, J. Psychiat. Res., 2010, 44, 808–816 http://dx.doi.org/10.1016/j.jpsychires.2010.01.00510.1016/j.jpsychires.2010.01.005Search in Google Scholar PubMed

[45] Bulygina V.V., Shishkina G.T., Berezova I.V., Dygalo N.N., BDNF protein expression in the hippocampus following exposure of rats to forced swimming stress, Dokl. Biol. Sci., 2011, 437, 82–84 http://dx.doi.org/10.1134/S001249661102011610.1134/S0012496611020116Search in Google Scholar PubMed

[46] Shi S.S., Shao S.H., Yuan B.P., Pan F., Li Z.L., Acute stress and chronic stress change brain-derived neurotrophic factor (BDNF) and tyrosine kinase-coupled receptor (TrkB) expression in both young and aged rat hippocampus, Yonsei Med. J., 2010, 51, 661–671 http://dx.doi.org/10.3349/ymj.2010.51.5.66110.3349/ymj.2010.51.5.661Search in Google Scholar PubMed PubMed Central

[47] Uysal N., Sisman A.R., Dayi A., Ozbal S., Cetin F., Baykara B., et al., Acute footshock-stress increases spatial learning-memory and correlates to increased hippocampal BDNF and VEGF and cell numbers in adolescent male and female rats, Neurosci. Lett., 2012, 514, 141–146 http://dx.doi.org/10.1016/j.neulet.2012.02.04910.1016/j.neulet.2012.02.049Search in Google Scholar PubMed

[48] Neto F.L., Borges G., Torres-Sanchez S., Mico J.A., Berrocoso E., Neurotrophins role in depression neurobiology: a review of basic and clinical evidence, Curr. Neuropharmacol., 2011, 9, 530–552 http://dx.doi.org/10.2174/15701591179837626210.2174/157015911798376262Search in Google Scholar PubMed PubMed Central

[49] Coppens C.M., Siripornmongcolchai T., Wibrand K., Alme M.N., Buwalda B., de Boer S.F., et al., Social defeat during adolescence and adulthood differentially induce BDNF-regulated immediate early genes, Front. Behav. Neurosci., 2011, 5, 72 http://dx.doi.org/10.3389/fnbeh.2011.0007210.3389/fnbeh.2011.00072Search in Google Scholar PubMed PubMed Central

[50] Fanous S., Hammer R.P., Jr., Nikulina E.M., Short- and long-term effects of intermittent social defeat stress on brain-derived neurotrophic factor expression in mesocorticolimbic brain regions, Neuroscience, 2010, 167, 598–607 http://dx.doi.org/10.1016/j.neuroscience.2010.02.06410.1016/j.neuroscience.2010.02.064Search in Google Scholar PubMed PubMed Central

[51] Berton O., McClung C.A., Dileone R.J., Krishnan V., Renthal W., Russo S.J., et al., Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress, Science, 2006, 311, 864–868 http://dx.doi.org/10.1126/science.112097210.1126/science.1120972Search in Google Scholar PubMed

[52] Duman R.S., Heninger G.R., Nestler E.J., A molecular and cellular theory of depression, Arch. Gen. Psychiat., 1997, 54, 597–606 http://dx.doi.org/10.1001/archpsyc.1997.0183019001500210.1001/archpsyc.1997.01830190015002Search in Google Scholar

[53] Duman R.S., Monteggia L.M., A neurotrophic model for stress-related mood disorders, Biol. Psychiat., 2006, 59, 1116–1127 http://dx.doi.org/10.1016/j.biopsych.2006.02.01310.1016/j.biopsych.2006.02.013Search in Google Scholar

[54] Krishnan V., Nestler E.J., The molecular neurobiology of depression, Nature, 2008, 455, 894–902 http://dx.doi.org/10.1038/nature0745510.1038/nature07455Search in Google Scholar

[55] Coppell A.L., Pei Q., Zetterstrom T.S., Bi-phasic change in BDNF gene expression following antidepressant drug treatment, Neuropharmacology, 2003, 44, 903–910 http://dx.doi.org/10.1016/S0028-3908(03)00077-710.1016/S0028-3908(03)00077-7Search in Google Scholar

[56] Molteni R., Calabrese F., Bedogni F., Tongiorgi E., Fumagalli F., Racagni G., et al., Chronic treatment with fluoxetine up-regulates cellular BDNF mRNA expression in rat dopaminergic regions, Int. J. Neuropsychopharmacol., 2006, 9, 307–317 http://dx.doi.org/10.1017/S146114570500576610.1017/S1461145705005766Search in Google Scholar PubMed

[57] Ferris L.T., Williams J.S., Shen C.L., The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function, Med. Sci. Sports Exerc., 2007, 39, 728–734 http://dx.doi.org/10.1249/mss.0b013e31802f04c710.1249/mss.0b013e31802f04c7Search in Google Scholar PubMed

[58] Marais L., Stein D.J., Daniels W.M., Exercise increases BDNF levels in the striatum and decreases depressive-like behavior in chronically stressed rats, Metab. Brain Dis., 2009, 24, 587–597 http://dx.doi.org/10.1007/s11011-009-9157-210.1007/s11011-009-9157-2Search in Google Scholar PubMed

[59] Kazlauckas V., Pagnussat N., Mioranzza S., Kalinine E., Nunes F., Pettenuzzo L., et al., Enriched environment effects on behavior, memory and BDNF in low and high exploratory mice, Physiol. Behav., 2011, 102, 475–480 http://dx.doi.org/10.1016/j.physbeh.2010.12.02510.1016/j.physbeh.2010.12.025Search in Google Scholar PubMed

[60] Yang C., Hu Y.M., Zhou Z.Q., Zhang G.F., Yang J.J., Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test, Ups. J. Med. Sci., 2012, Epub ahead of print, doi: 10.3109/03009734.2012.724118 10.3109/03009734.2012.724118Search in Google Scholar PubMed PubMed Central

[61] Monteggia L.M., Barrot M., Powell C.M., Berton O., Galanis V., Gemelli T., et al., Essential role of brain-derived neurotrophic factor in adult hippocampal function, Proc. Natl. Acad. Sci. USA, 2004, 101, 10827–10832 http://dx.doi.org/10.1073/pnas.040214110110.1073/pnas.0402141101Search in Google Scholar PubMed PubMed Central

[62] Chen Z.Y., Jing D., Bath K.G., Ieraci A., Khan T., Siao C.J., et al., Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior, Science, 2006, 314, 140–143 http://dx.doi.org/10.1126/science.112966310.1126/science.1129663Search in Google Scholar PubMed PubMed Central

[63] Saarelainen T., Hendolin P., Lucas G., Koponen E., Sairanen M., MacDonald E., et al., 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 10.1523/JNEUROSCI.23-01-00349.2003Search in Google Scholar

[64] Rantamaki T., Hendolin P., Kankaanpaa A., Mijatovic J., Piepponen P., Domenici E., et al., Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain, Neuropsychopharmacology, 2007, 32, 2152–2162 http://dx.doi.org/10.1038/sj.npp.130134510.1038/sj.npp.1301345Search in Google Scholar PubMed

[65] Rantamaki T., Vesa L., Antila H., Di Lieto A., Tammela P., Schmitt A., et al., Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade, PLoS One, 2011, 6, e20567 http://dx.doi.org/10.1371/journal.pone.002056710.1371/journal.pone.0020567Search in Google Scholar PubMed PubMed Central

[66] Eisch A.J., Bolanos C.A., de Wit J., Simonak R.D., Pudiak C.M., Barrot M., et al., Brain-derived neurotrophic factor in the ventral midbrainnucleus accumbens pathway: a role in depression, Biol. Psychiat., 2003, 54, 994–1005 http://dx.doi.org/10.1016/j.biopsych.2003.08.00310.1016/j.biopsych.2003.08.003Search in Google Scholar PubMed

[67] Shirayama Y., Chen A.C., Nakagawa S., Russell D.S., Duman R.S., Brainderived neurotrophic factor produces antidepressant effects in behavioral models of depression, J. Neurosci., 2002, 22, 3251–3261 10.1523/JNEUROSCI.22-08-03251.2002Search in Google Scholar

[68] Hoshaw B.A., Malberg J.E., Lucki I., Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects, Brain. Res., 2005, 1037, 204–208 http://dx.doi.org/10.1016/j.brainres.2005.01.00710.1016/j.brainres.2005.01.007Search in Google Scholar PubMed

[69] Govindarajan A., Rao B.S., Nair D., Trinh M., Mawjee N., Tonegawa S., et al., Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects, Proc. Natl. Acad. Sci. USA, 2006, 103, 13208–13213 http://dx.doi.org/10.1073/pnas.060518010310.1073/pnas.0605180103Search in Google Scholar PubMed PubMed Central

[70] Taliaz D., Loya A., Gersner R., Haramati S., Chen A., Zangen A., Resilience to chronic stress is mediated by hippocampal brainderived neurotrophic factor, J. Neurosci., 2011, 31, 4475–4483 http://dx.doi.org/10.1523/JNEUROSCI.5725-10.201110.1523/JNEUROSCI.5725-10.2011Search in Google Scholar PubMed PubMed Central

[71] Schmidt H.D., Duman R.S., Peripheral BDNF produces antidepressant-like effects in cellular and behavioral models, Neuropsychopharmacology, 2010, 35, 2378–2391 http://dx.doi.org/10.1038/npp.2010.11410.1038/npp.2010.114Search in Google Scholar PubMed PubMed Central

[72] Ernfors P., Lee K.F., Jaenisch R., Mice lacking brain-derived neurotrophic factor develop with sensory deficits, Nature, 1994, 368, 147–150 http://dx.doi.org/10.1038/368147a010.1038/368147a0Search in Google Scholar PubMed

[73] MacQueen G.M., Ramakrishnan K., Croll S.D., Siuciak J.A., Yu G., Young L.T., et al., Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression, Behav. Neurosci., 2001, 115, 1145–1153 http://dx.doi.org/10.1037/0735-7044.115.5.114510.1037/0735-7044.115.5.1145Search in Google Scholar

[74] Chourbaji S., Hellweg R., Brandis D., Zorner B., Zacher C., Lang U.E., et al., Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior, Mol. Brain Res., 2004, 121, 28–36 http://dx.doi.org/10.1016/j.molbrainres.2003.11.00210.1016/j.molbrainres.2003.11.002Search in Google Scholar PubMed

[75] Ibarguen-Vargas Y., Surget A., Vourc’h P., Leman S., Andres C.R., Gardier A.M., et al., Deficit in BDNF does not increase vulnerability to stress but dampens antidepressant-like effects in the unpredictable chronic mild stress, Behav. Brain Res., 2009, 202, 245–251 http://dx.doi.org/10.1016/j.bbr.2009.03.04010.1016/j.bbr.2009.03.040Search in Google Scholar PubMed

[76] Advani T., Koek W., Hensler J.G., Gender differences in the enhanced vulnerability of BDNF+/- mice to mild stress, Int. J. Neuropsychopharmacol., 2009, 12, 583–588 http://dx.doi.org/10.1017/S146114570900024810.1017/S1461145709000248Search in Google Scholar PubMed

[77] Magarinos A.M., Li C.J., Gal Toth J., Bath K.G., Jing D., Lee F.S., et al., Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons, Hippocampus, 2011, 21, 253–264 http://dx.doi.org/10.1002/hipo.2074410.1002/hipo.20744Search in Google Scholar PubMed PubMed Central

[78] Taliaz D., Nagaraj V., Haramati S., Chen A., Zangen A., Altered brainderived neurotrophic factor expression in the ventral tegmental area, but not in the hippocampus, is essential for antidepressant-like effects of electroconvulsive therapy, Biol. Psychiat., 2012, Epub ahead of print, doi: 10.1016/j.biopsych.2012.07.025 10.1016/j.biopsych.2012.07.025Search in Google Scholar PubMed

[79] Monteggia L.M., Luikart B., Barrot M., Theobold D., Malkovska I., Nef S., et al., Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors, Biol. Psychiat., 2007, 61, 187–197 http://dx.doi.org/10.1016/j.biopsych.2006.03.02110.1016/j.biopsych.2006.03.021Search in Google Scholar PubMed

[80] Adachi M., Barrot M., Autry A.E., Theobald D., Monteggia L.M., Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy, Biol. Psychiat., 2008, 63, 642–649 http://dx.doi.org/10.1016/j.biopsych.2007.09.01910.1016/j.biopsych.2007.09.019Search in Google Scholar PubMed PubMed Central

[81] Taliaz D., Stall N., Dar D.E., Zangen A., Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis, Mol. Psychiatr., 2010, 15, 80–92 http://dx.doi.org/10.1038/mp.2009.6710.1038/mp.2009.67Search in Google Scholar PubMed PubMed Central

[82] Egan M.F., Kojima M., Callicott J.H., Goldberg T.E., Kolachana B.S., Bertolino A., et al., The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function, Cell, 2003, 112, 257–269 http://dx.doi.org/10.1016/S0092-8674(03)00035-710.1016/S0092-8674(03)00035-7Search in Google Scholar

[83] Chen Z.Y., Bath K., McEwen B., Hempstead B., Lee F., Impact of genetic variant BDNF (Val66Met) on brain structure and function, Novartis Found. Symp., 2008, 289, 180–188, discussion 188–195 http://dx.doi.org/10.1002/9780470751251.ch1410.1002/9780470751251.ch14Search in Google Scholar PubMed PubMed Central

[84] Chiaruttini C., Vicario A., Li Z., Baj G., Braiuca P., Wu Y., et al., Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation, Proc. Natl. Acad. Sci. USA, 2009, 106, 16481–16486 http://dx.doi.org/10.1073/pnas.090283310610.1073/pnas.0902833106Search in Google Scholar PubMed PubMed Central

[85] Hariri A.R., Goldberg T.E., Mattay V.S., Kolachana B.S., Callicott J.H., Egan M.F., et al., Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance, J. Neurosci., 2003, 23, 6690–6694 10.1523/JNEUROSCI.23-17-06690.2003Search in Google Scholar

[86] Frodl T., Schule C., Schmitt G., Born C., Baghai T., Zill P., et al., Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression, Arch. Gen. Psychiat., 2007, 64, 410–416 http://dx.doi.org/10.1001/archpsyc.64.4.41010.1001/archpsyc.64.4.410Search in Google Scholar PubMed

[87] Montag C., Weber B., Fliessbach K., Elger C., Reuter M., The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: incremental support for a genetic risk factor for depression, Psychol. Med., 2009, 39, 1831–1839 http://dx.doi.org/10.1017/S003329170900550910.1017/S0033291709005509Search in Google Scholar PubMed

[88] Lang U.E., Hellweg R., Sander T., Gallinat J., The Met allele of the BDNF Val66Met polymorphism is associated with increased BDNF serum concentrations, Mol. Psychiatr., 2009, 14, 120–122 http://dx.doi.org/10.1038/mp.2008.8010.1038/mp.2008.80Search in Google Scholar PubMed

[89] Hajek T., Kopecek M., Hoschl C., Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: meta-analysis, World J. Biol. Psychiatry, 2012, 13, 178–187 http://dx.doi.org/10.3109/15622975.2011.58000510.3109/15622975.2011.580005Search in Google Scholar PubMed PubMed Central

[90] Jessen F., Schuhmacher A., von Widdern O., Guttenthaler V., Hofels S., Suliman H., et al., No association of the Val66Met polymorphism of the brain-derived neurotrophic factor with hippocampal volume in major depression, Psychiatr. Genet., 2009, 19, 99–101 http://dx.doi.org/10.1097/YPG.0b013e32832080ce10.1097/YPG.0b013e32832080ceSearch in Google Scholar PubMed

[91] Terracciano A., Martin B., Ansari D., Tanaka T., Ferrucci L., Maudsley S., et al., Plasma BDNF concentration, Val66Met genetic variant and depression-related personality traits, Genes Brain Behav., 2010, 9, 512–518 10.1111/j.1601-183X.2010.00579.xSearch in Google Scholar PubMed PubMed Central

[92] Yoshimura R., Kishi T., Suzuki A., Umene-Nakano W., Ikenouchi-Sugita A., Hori H., et al., The brain-derived neurotrophic factor (BDNF) polymorphism Val66Met is associated with neither serum BDNF level nor response to selective serotonin reuptake inhibitors in depressed Japanese patients, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2011, 35, 1022–1025 http://dx.doi.org/10.1016/j.pnpbp.2011.02.00910.1016/j.pnpbp.2011.02.009Search in Google Scholar PubMed

[93] Sarchiapone M., Carli V., Roy A., Iacoviello L., Cuomo C., Latella M.C., et al., Association of polymorphism (Val66Met) of brain-derived neurotrophic factor with suicide attempts in depressed patients, Neuropsychobiology, 2008, 57, 139–145 http://dx.doi.org/10.1159/00014236110.1159/000142361Search in Google Scholar PubMed

[94] Gatt J.M., Nemeroff C.B., Dobson-Stone C., Paul R.H., Bryant R.A., Schofield P.R., et al., Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety, Mol. Psychiatr., 2009, 14, 681–695 http://dx.doi.org/10.1038/mp.2008.14310.1038/mp.2008.143Search in Google Scholar PubMed

[95] Choi M.J., Kang R.H., Lim S.W., Oh K.S., Lee M.S., Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder, Brain Res., 2006, 1118, 176–182 http://dx.doi.org/10.1016/j.brainres.2006.08.01210.1016/j.brainres.2006.08.012Search in Google Scholar PubMed

[96] Tsai S.J., Hong C.J., Liou Y.J., Effects of BDNF polymorphisms on antidepressant action, Psychiatry Investig., 2010, 7, 236–242 http://dx.doi.org/10.4306/pi.2010.7.4.23610.4306/pi.2010.7.4.236Search in Google Scholar PubMed PubMed Central

[97] Krishnan V., Han M.H., Graham D.L., Berton O., Renthal W., Russo S.J., et al., Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions, Cell, 2007, 131, 391–404 http://dx.doi.org/10.1016/j.cell.2007.09.01810.1016/j.cell.2007.09.018Search in Google Scholar PubMed

[98] Liu R.J., Lee F.S., Li X.Y., Bambico F., Duman R.S., Aghajanian G.K., Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex, Biol. Psychiatry, 2012, 71, 996–1005 http://dx.doi.org/10.1016/j.biopsych.2011.09.03010.1016/j.biopsych.2011.09.030Search in Google Scholar PubMed PubMed Central

[99] Bath K.G., Jing D.Q., Dincheva I., Neeb C.C., Pattwell S.S., Chao M.V., et al., BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity, Neuropsychopharmacology, 2012, 37, 1297–1304 http://dx.doi.org/10.1038/npp.2011.31810.1038/npp.2011.318Search in Google Scholar PubMed PubMed Central

[100] Ninan I., Bath K.G., Dagar K., Perez-Castro R., Plummer M.R., Lee F.S., et al., The BDNF Val66Met polymorphism impairs NMDA receptordependent synaptic plasticity in the hippocampus, J. Neurosci., 2010, 30, 8866–8870 http://dx.doi.org/10.1523/JNEUROSCI.1405-10.201010.1523/JNEUROSCI.1405-10.2010Search in Google Scholar PubMed PubMed Central

[101] Yu H., Wang D.D., Wang Y., Liu T., Lee F.S., Chen Z.Y., Variant brainderived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants, J. Neurosci., 2012, 32, 4092–4101 http://dx.doi.org/10.1523/JNEUROSCI.5048-11.201210.1523/JNEUROSCI.5048-11.2012Search in Google Scholar PubMed PubMed Central

[102] Wojnar M., Brower K.J., Strobbe S., Ilgen M., Matsumoto H., Nowosad I., et al., Association between Val66Met brain-derived neurotrophic factor (BDNF) gene polymorphism and post-treatment relapse in alcohol dependence, Alcohol. Clin. Exp. Res., 2009, 33, 693–702 http://dx.doi.org/10.1111/j.1530-0277.2008.00886.x10.1111/j.1530-0277.2008.00886.xSearch in Google Scholar PubMed PubMed Central

[103] Jia W., Shi J.G., Wu B., Ao L., Zhang R., Zhu Y.S., Polymorphisms of brain-derived neurotrophic factor associated with heroin dependence, Neurosci. Lett., 2011, 495, 221–224 http://dx.doi.org/10.1016/j.neulet.2011.03.07210.1016/j.neulet.2011.03.072Search in Google Scholar PubMed

[104] Chen J., Li X., McGue M., Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression, Genes Brain Behav., 2012, Epub ahead of print, doi: 10.1111/j.1601-183X.2012.00843.x 10.1111/j.1601-183X.2012.00843.xSearch in Google Scholar PubMed

[105] von Bohlen und Halbach O., Krause S., Medina D., Sciarretta C., Minichiello L., Unsicker K., Regional- and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies, Biol. Psychiatry, 2006, 59, 793–800 http://dx.doi.org/10.1016/j.biopsych.2005.08.02510.1016/j.biopsych.2005.08.025Search in Google Scholar PubMed

[106] Bergami M., Berninger B., Canossa M., Conditional deletion of TrkB alters adult hippocampal neurogenesis and anxiety-related behavior, Commun. Integr. Biol., 2009, 2, 14–16 http://dx.doi.org/10.4161/cib.2.1.734910.4161/cib.2.1.7349Search in Google Scholar PubMed PubMed Central

[107] Koponen E., Lakso M., Castren E., Overexpression of the full-length neurotrophin receptor trkB regulates the expression of plasticityrelated genes in mouse brain, Mol. Brain Res., 2004, 130, 81–94 http://dx.doi.org/10.1016/j.molbrainres.2004.07.01010.1016/j.molbrainres.2004.07.010Search in Google Scholar PubMed

[108] Dwivedi Y., Rizavi H.S., Roberts R.C., Conley R.C., Tamminga C.A., Pandey G.N., Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects, J. Neurochem., 2001, 77, 916–928 http://dx.doi.org/10.1046/j.1471-4159.2001.00300.x10.1046/j.1471-4159.2001.00300.xSearch in Google Scholar PubMed

[109] Yuan P., Zhou R., Wang Y., Li X., Li J., Chen G., et al., Altered levels of extracellular signal-regulated kinase signaling proteins in postmortem frontal cortex of individuals with mood disorders and schizophrenia, J. Affect. Disord., 2010, 124, 164–169 http://dx.doi.org/10.1016/j.jad.2009.10.01710.1016/j.jad.2009.10.017Search in Google Scholar PubMed PubMed Central

[110] Qi X., Lin W., Wang D., Pan Y., Wang W., Sun M., A role for the extracellular signal-regulated kinase signal pathway in depressivelike behavior, Behav. Brain Res., 2009, 199, 203–209 http://dx.doi.org/10.1016/j.bbr.2008.11.05110.1016/j.bbr.2008.11.051Search in Google Scholar PubMed

[111] First M., Gil-Ad I., Taler M., Tarasenko I., Novak N., Weizman A., The effects of fluoxetine treatment in a chronic mild stress rat model on depression-related behavior, brain neurotrophins and ERK expression, J. Mol. Neurosci., 2011, 45, 246–255 http://dx.doi.org/10.1007/s12031-011-9515-510.1007/s12031-011-9515-5Search in Google Scholar PubMed

[112] Qi X., Lin W., Li J., Li H., Wang W., Wang D., et al., Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress, Neurobiol. Dis., 2008, 31, 278–285 http://dx.doi.org/10.1016/j.nbd.2008.05.00310.1016/j.nbd.2008.05.003Search in Google Scholar PubMed

[113] Duric V., Banasr M., Licznerski P., Schmidt H.D., Stockmeier C.A., Simen A.A., et al., A negative regulator of MAP kinase causes depressive behavior, Nat. Med., 2010, 16, 1328–1332 http://dx.doi.org/10.1038/nm.221910.1038/nm.2219Search in Google Scholar PubMed PubMed Central

[114] Iniguez S.D., Vialou V., Warren B.L., Cao J.L., Alcantara L.F., Davis L.C., et al., Extracellular signal-regulated kinase-2 within the ventral tegmental area regulates responses to stress, J. Neurosci., 2010, 30, 7652–7663 http://dx.doi.org/10.1523/JNEUROSCI.0951-10.201010.1523/JNEUROSCI.0951-10.2010Search in Google Scholar PubMed PubMed Central

[115] Karege F., Perroud N., Burkhardt S., Schwald M., Ballmann E., La Harpe R., et al., Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3beta in ventral prefrontal cortex of depressed suicide victims, Biol. Psychiatry, 2007, 61, 240–245 http://dx.doi.org/10.1016/j.biopsych.2006.04.03610.1016/j.biopsych.2006.04.036Search in Google Scholar PubMed

[116] Dwivedi Y., Rizavi H.S., Zhang H., Roberts R.C., Conley R.R., Pandey G.N., Modulation in activation and expression of phosphatase and tensin homolog on chromosome ten, Akt1, and 3-phosphoinositidedependent kinase 1: further evidence demonstrating altered phosphoinositide 3-kinase signaling in postmortem brain of suicide subjects, Biol. Psychiatry, 2010, 67, 1017–1025 http://dx.doi.org/10.1016/j.biopsych.2009.12.03110.1016/j.biopsych.2009.12.031Search in Google Scholar PubMed PubMed Central

[117] Chandran A., Iyo A.H., Jernigan C.S., Legutko B., Austin M.C., Karolewicz B., Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress, Prog. Neuropsychopharmacol. Biol. Psychiatry, 2012, 40C, 240–245 10.1016/j.pnpbp.2012.08.001Search in Google Scholar PubMed PubMed Central

[118] Krishnan V., Han M.H., Mazei-Robison M., Iniguez S.D., Ables J.L., Vialou V., et al., AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli, Biol. Psychiatry, 2008, 64, 691–700 http://dx.doi.org/10.1016/j.biopsych.2008.06.00310.1016/j.biopsych.2008.06.003Search in Google Scholar PubMed PubMed Central

[119] Shi H.S., Zhu W.L., Liu J.F., Luo Y.X., Si J.J., Wang S.J., et al., PI3K/Akt signaling pathway in the basolateral amygdala mediates the rapid antidepressant-like effects of trefoil factor 3, Neuropsychopharmacology, 2012, 37, 2671–2683 http://dx.doi.org/10.1038/npp.2012.13110.1038/npp.2012.131Search in Google Scholar PubMed PubMed Central

[120] Bruel-Jungerman E., Veyrac A., Dufour F., Horwood J., Laroche S., Davis S., Inhibition of PI3K-Akt signaling blocks exercise-mediated enhancement of adult neurogenesis and synaptic plasticity in the dentate gyrus, PLoS One, 2009, 4, e7901 http://dx.doi.org/10.1371/journal.pone.000790110.1371/journal.pone.0007901Search in Google Scholar PubMed PubMed Central

[121] Budni J., Lobato K.R., Binfare R.W., Freitas A.E., Costa A.P., Martinde-Saavedra M.D., et al., Involvement of PI3K, GSK-3beta and PPARgamma in the antidepressant-like effect of folic acid in the forced swimming test in mice, J. Psychopharmacol., 2012, 26, 714–723 http://dx.doi.org/10.1177/026988111142445610.1177/0269881111424456Search in Google Scholar PubMed

[122] Li N., Lee B., Liu R.J., Banasr M., Dwyer J.M., Iwata M., et al., mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists, Science, 2010, 329, 959–964 http://dx.doi.org/10.1126/science.119028710.1126/science.1190287Search in Google Scholar PubMed PubMed Central

[123] Li N., Liu R.J., Dwyer J.M., Banasr M., Lee B., Son H., et al., Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure, Biol. Psychiatry, 2011, 69, 754–761 http://dx.doi.org/10.1016/j.biopsych.2010.12.01510.1016/j.biopsych.2010.12.015Search in Google Scholar PubMed PubMed Central

[124] Autry A.E., Adachi M., Nosyreva E., Na E.S., Los M.F., Cheng P.F., et al., NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses, Nature, 2011, 475, 91–95 http://dx.doi.org/10.1038/nature1013010.1038/nature10130Search in Google Scholar PubMed PubMed Central

[125] Karege F., Perroud N., Burkhardt S., Fernandez R., Ballmann E., La Harpe R., et al., Protein levels of beta-catenin and activation state of glycogen synthase kinase-3beta in major depression. A study with postmortem prefrontal cortex, J. Affect. Disord., 2012, 136, 185–188 http://dx.doi.org/10.1016/j.jad.2011.09.02410.1016/j.jad.2011.09.024Search in Google Scholar PubMed

[126] Inkster B., Nichols T.E., Saemann P.G., Auer D.P., Holsboer F., Muglia P., et al., Association of GSK3beta polymorphisms with brain structural changes in major depressive disorder, Arch. Gen. Psychiat., 2009, 66, 721–728 http://dx.doi.org/10.1001/archgenpsychiatry.2009.7010.1001/archgenpsychiatry.2009.70Search in Google Scholar PubMed

[127] Gould T.D., Einat H., Bhat R., Manji H.K., AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test, Int. J. Neuropsychopharmacol., 2004, 7, 387–390 http://dx.doi.org/10.1017/S146114570400453510.1017/S1461145704004535Search in Google Scholar PubMed

[128] Kaidanovich-Beilin O., Milman A., Weizman A., Pick C.G., Eldar-Finkelman H., Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus, Biol. Psychiatry, 2004, 55, 781–784 http://dx.doi.org/10.1016/j.biopsych.2004.01.00810.1016/j.biopsych.2004.01.008Search in Google Scholar PubMed

[129] Kaidanovich-Beilin O., Lipina T.V., Takao K., van Eede M., Hattori S., Laliberte C., et al., Abnormalities in brain structure and behavior in GSK-3alpha mutant mice, Mol. Brain, 2009, 2, 35 http://dx.doi.org/10.1186/1756-6606-2-3510.1186/1756-6606-2-35Search in Google Scholar PubMed PubMed Central

[130] O’Brien W.T., Harper A.D., Jove F., Woodgett J.R., Maretto S., Piccolo S., et al., Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium, J. Neurosci., 2004, 24, 6791–6798 http://dx.doi.org/10.1523/JNEUROSCI.4753-03.200410.1523/JNEUROSCI.4753-03.2004Search in Google Scholar PubMed PubMed Central

[131] Polter A., Beurel E., Yang S., Garner R., Song L., Miller C.A., et al., Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances, Neuropsychopharmacology, 2010, 35, 1761–1774 10.1038/npp.2010.43Search in Google Scholar PubMed PubMed Central

[132] Beurel E., Song L., Jope R.S., Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice, Mol. Psychiatr., 2011, 16, 1068–1070 http://dx.doi.org/10.1038/mp.2011.4710.1038/mp.2011.47Search in Google Scholar

[133] Gould T.D., O’Donnell K.C., Picchini A.M., Dow E.R., Chen G., Manji H.K., Generation and behavioral characterization of beta-catenin forebrain-specific conditional knock-out mice, Behav. Brain Res., 2008, 189, 117–125 http://dx.doi.org/10.1016/j.bbr.2007.12.02810.1016/j.bbr.2007.12.028Search in Google Scholar

[134] Gould T.D., Einat H., O’Donnell K.C., Picchini A.M., Schloesser R.J., Manji H.K., Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors, Neuropsychopharmacology, 2007, 32, 2173–2183 http://dx.doi.org/10.1038/sj.npp.130133810.1038/sj.npp.1301338Search in Google Scholar

[135] Duman R.S., Pathophysiology of depression: the concept of synaptic plasticity, Eur. Psychiatry, 2002, 17,Suppl. 3, 306–310 http://dx.doi.org/10.1016/S0924-9338(02)00654-510.1016/S0924-9338(02)00654-5Search in Google Scholar

[136] Sheline Y.I., Wang P.W., Gado M.H., Csernansky J.G., Vannier M.W., Hippocampal atrophy in recurrent major depression, Proc. Natl. Acad. Sci. USA, 1996, 93, 3908–3913 http://dx.doi.org/10.1073/pnas.93.9.390810.1073/pnas.93.9.3908Search in Google Scholar PubMed PubMed Central

[137] Bremner J.D., Narayan M., Anderson E.R., Staib L.H., Miller H.L., Charney D.S., Hippocampal volume reduction in major depression, Am. J. Psychiatry, 2000, 157, 115–118 http://dx.doi.org/10.1176/appi.ajp.157.7.112010.1176/appi.ajp.157.7.1120Search in Google Scholar PubMed

[138] Frodl T., Meisenzahl E.M., Zetzsche T., Born C., Groll C., Jager M., et al., Hippocampal changes in patients with a first episode of major depression, Am. J. Psychiatry, 2002, 159, 1112–1118 http://dx.doi.org/10.1176/appi.ajp.159.7.111210.1176/appi.ajp.159.7.1112Search in Google Scholar PubMed

[139] MacQueen G.M., Campbell S., McEwen B.S., Macdonald K., Amano S., Joffe R.T., et al., Course of illness, hippocampal function, and hippocampal volume in major depression, Proc. Natl. Acad. Sci. USA, 2003, 100, 1387–1392 http://dx.doi.org/10.1073/pnas.033748110010.1073/pnas.0337481100Search in Google Scholar PubMed PubMed Central

[140] Campbell S., Macqueen G., The role of the hippocampus in the pathophysiology of major depression, J. Psychiatry Neurosci., 2004, 29, 417–426 Search in Google Scholar

[141] Videbech P., Ravnkilde B., Hippocampal volume and depression: a meta-analysis of MRI studies, Am. J. Psychiatry, 2004, 161, 1957–1966 http://dx.doi.org/10.1176/appi.ajp.161.11.195710.1176/appi.ajp.161.11.1957Search in Google Scholar PubMed

[142] Fuchs E., Flugge G., Czeh B., Remodeling of neuronal networks by stress, Front. Biosci., 2006, 11, 2746–2758 http://dx.doi.org/10.2741/200410.2741/2004Search in Google Scholar PubMed

[143] Radley J.J., Rocher A.B., Miller M., Janssen W.G., Liston C., Hof P.R., et al., Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex, Cereb. Cortex, 2006, 16, 313–320 http://dx.doi.org/10.1093/cercor/bhi10410.1093/cercor/bhi104Search in Google Scholar

[144] Izquierdo A., Wellman C.L., Holmes A., Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice, J. Neurosci., 2006, 26, 5733–5738 http://dx.doi.org/10.1523/JNEUROSCI.0474-06.200610.1523/JNEUROSCI.0474-06.2006Search in Google Scholar

[145] Lamont S.R., Paulls A., Stewart C.A., Repeated electroconvulsive stimulation, but not antidepressant drugs, induces mossy fibre sprouting in the rat hippocampus, Brain Res., 2001, 893, 53–58 http://dx.doi.org/10.1016/S0006-8993(00)03287-X10.1016/S0006-8993(00)03287-XSearch in Google Scholar

[146] Norrholm S.D., Ouimet C.C., Altered dendritic spine density in animal models of depression and in response to antidepressant treatment, Synapse, 2001, 42, 151–163 http://dx.doi.org/10.1002/syn.1000610.1002/syn.10006Search in Google Scholar

[147] Hajszan T., MacLusky N.J., Leranth C., Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus, Eur. J. Neurosci., 2005, 21, 1299–1303 http://dx.doi.org/10.1111/j.1460-9568.2005.03968.x10.1111/j.1460-9568.2005.03968.xSearch in Google Scholar

[148] Duman R.S., Aghajanian G.K., Synaptic dysfunction in depression: potential therapeutic targets, Science, 2012, 338, 68–72 http://dx.doi.org/10.1126/science.122293910.1126/science.1222939Search in Google Scholar

[149] Tolwani R.J., Buckmaster P.S., Varma S., Cosgaya J.M., Wu Y., Suri C., et al., BDNF overexpression increases dendrite complexity in hippocampal dentate gyrus, Neuroscience, 2002, 114, 795–805 http://dx.doi.org/10.1016/S0306-4522(02)00301-910.1016/S0306-4522(02)00301-9Search in Google Scholar

[150] Kumar V., Zhang M.X., Swank M.W., Kunz J., Wu G.Y., Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways, J. Neurosci., 2005, 25, 11288–11299 http://dx.doi.org/10.1523/JNEUROSCI.2284-05.200510.1523/JNEUROSCI.2284-05.2005Search in Google Scholar

[151] Rodgers E.E., Theibert A.B., Functions of PI 3-kinase in development of the nervous system, Int. J. Dev. Neurosci., 2002, 20, 187–197 http://dx.doi.org/10.1016/S0736-5748(02)00047-310.1016/S0736-5748(02)00047-3Search in Google Scholar

[152] Golden S.A., Russo S.J., Mechanisms of psychostimulant-induced structural plasticity, Cold Spring Harb. Perspect. Med., 2012, 2, pii: a011957 10.1101/cshperspect.a011957Search in Google Scholar PubMed PubMed Central

[153] Dietz D.M., Dietz K.C., Nestler E.J., Russo S.J., Molecular mechanisms of psychostimulant-induced structural plasticity, Pharmacopsychiatry, 2009, 42Suppl. 1, S69–78 http://dx.doi.org/10.1055/s-0029-120284710.1055/s-0029-1202847Search in Google Scholar PubMed PubMed Central

[154] Giachello C.N., Fiumara F., Giacomini C., Corradi A., Milanese C., Ghirardi M., et al., MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity, J. Cell Sci., 2010, 123, 881–893 http://dx.doi.org/10.1242/jcs.05684610.1242/jcs.056846Search in Google Scholar PubMed

[155] Malberg J.E., Duman R.S., Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment, Neuropsychopharmacology, 2003, 28, 1562–1571 http://dx.doi.org/10.1038/sj.npp.130023410.1038/sj.npp.1300234Search in Google Scholar PubMed

[156] Santarelli L., Saxe M., Gross C., Surget A., Battaglia F., Dulawa S., et al., Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants, Science, 2003, 301, 805–809 http://dx.doi.org/10.1126/science.108332810.1126/science.1083328Search in Google Scholar PubMed

[157] Surget A., Saxe M., Leman S., Ibarguen-Vargas Y., Chalon S., Griebel G., et al., Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal, Biol. Psychiatry, 2008, 64, 293–301 http://dx.doi.org/10.1016/j.biopsych.2008.02.02210.1016/j.biopsych.2008.02.022Search in Google Scholar PubMed

[158] Overstreet D.H., Fredericks K., Knapp D., Breese G., McMichael J., Nerve growth factor (NGF) has novel antidepressant-like properties in rats, Pharmacol. Biochem. Behav., 2010, 94, 553–560 http://dx.doi.org/10.1016/j.pbb.2009.11.01010.1016/j.pbb.2009.11.010Search in Google Scholar PubMed PubMed Central

[159] David D.J., Samuels B.A., Rainer Q., Wang J.W., Marsteller D., Mendez I., et al., Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression, Neuron, 2009, 62, 479–493 http://dx.doi.org/10.1016/j.neuron.2009.04.01710.1016/j.neuron.2009.04.017Search in Google Scholar PubMed PubMed Central

[160] Lee J., Duan W., Mattson M.P., 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., 2002, 82, 1367–1375 http://dx.doi.org/10.1046/j.1471-4159.2002.01085.x10.1046/j.1471-4159.2002.01085.xSearch in Google Scholar PubMed

[161] Rossi C., Angelucci A., Costantin L., Braschi C., Mazzantini M., Babbini F., et al., Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment, Eur. J. Neurosci., 2006, 24, 1850–1856 http://dx.doi.org/10.1111/j.1460-9568.2006.05059.x10.1111/j.1460-9568.2006.05059.xSearch in Google Scholar PubMed

[162] 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 http://dx.doi.org/10.1523/JNEUROSCI.3741-04.200510.1523/JNEUROSCI.3741-04.2005Search in Google Scholar PubMed PubMed Central

[163] Henry R.A., Hughes S.M., Connor B., AAV-mediated delivery of BDNF augments neurogenesis in the normal and quinolinic acid-lesioned adult rat brain, Eur. J. Neurosci., 2007, 25, 3513–3525 http://dx.doi.org/10.1111/j.1460-9568.2007.05625.x10.1111/j.1460-9568.2007.05625.xSearch in Google Scholar PubMed

[164] Zigova T., Pencea V., Wiegand S.J., Luskin M.B., Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb, Mol. Cell. Neurosci., 1998, 11, 234–245 http://dx.doi.org/10.1006/mcne.1998.068410.1006/mcne.1998.0684Search in Google Scholar PubMed

[165] 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 http://dx.doi.org/10.1016/j.expneurol.2004.11.01610.1016/j.expneurol.2004.11.016Search in Google Scholar PubMed

[166] Schabitz W.R., Steigleder T., Cooper-Kuhn C.M., Schwab S., Sommer C., Schneider A., et al., Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis, Stroke, 2007, 38, 2165–2172 http://dx.doi.org/10.1161/STROKEAHA.106.47733110.1161/STROKEAHA.106.477331Search in Google Scholar PubMed

[167] Shimazu K., Zhao M., Sakata K., Akbarian S., Bates B., Jaenisch R., et al., NT-3 facilitates hippocampal plasticity and learning and memory by regulating neurogenesis, Learn. Mem., 2006, 13, 307–315 http://dx.doi.org/10.1101/lm.7600610.1101/lm.76006Search in Google Scholar PubMed PubMed Central

[168] Frielingsdorf H., Simpson D.R., Thal L.J., Pizzo D.P., Nerve growth factor promotes survival of new neurons in the adult hippocampus, Neurobiol. Dis., 2007, 26, 47–55 http://dx.doi.org/10.1016/j.nbd.2006.11.01510.1016/j.nbd.2006.11.015Search in Google Scholar PubMed

[169] Fournier N.M., Lee B., Banasr M., Elsayed M., Duman R.S., Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling, Neuropharmacology, 2012, 63, 642–652 http://dx.doi.org/10.1016/j.neuropharm.2012.04.03310.1016/j.neuropharm.2012.04.033Search in Google Scholar PubMed PubMed Central

[170] Peltier J., O’Neill A., Schaffer D.V., PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation, Dev. Neurobiol., 2007, 67, 1348–1361 http://dx.doi.org/10.1002/dneu.2050610.1002/dneu.20506Search in Google Scholar PubMed

[171] Eom T.Y., Jope R.S., Blocked inhibitory serine-phosphorylation of glycogen synthase kinase-3alpha/beta impairs in vivo neural precursor cell proliferation, Biol. Psychiatry, 2009, 66, 494–502 http://dx.doi.org/10.1016/j.biopsych.2009.04.01510.1016/j.biopsych.2009.04.015Search in Google Scholar PubMed PubMed Central

[172] Sirerol-Piquer M., Gomez-Ramos P., Hernandez F., Perez M., Moran M.A., Fuster-Matanzo A., et al., GSK3beta overexpression induces neuronal death and a depletion of the neurogenic niches in the dentate gyrus, Hippocampus, 2011, 21, 910–922 10.1002/hipo.20805Search in Google Scholar PubMed

[173] Salton S.R., Ferri G.L., Hahm S., Snyder S.E., Wilson A.J., Possenti R., et al., VGF: a novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance, Front. Neuroendocrinol., 2000, 21, 199–219 http://dx.doi.org/10.1006/frne.2000.019910.1006/frne.2000.0199Search in Google Scholar

[174] Hunsberger J.G., Newton S.S., Bennett A.H., Duman C.H., Russell D.S., Salton S.R., et al., Antidepressant actions of the exerciseregulated gene VGF, Nat. Med., 2007, 13, 1476–1482 http://dx.doi.org/10.1038/nm166910.1038/nm1669Search in Google Scholar

[175] Thakker-Varia S., Krol J.J., Nettleton J., Bilimoria P.M., Bangasser D.A., Shors T.J., et al., The neuropeptide VGF produces antidepressant-like behavioral effects and enhances proliferation in the hippocampus, J. Neurosci., 2007, 27, 12156–12167 http://dx.doi.org/10.1523/JNEUROSCI.1898-07.200710.1523/JNEUROSCI.1898-07.2007Search in Google Scholar

[176] Calabrese F., Molteni R., Cattaneo A., Macchi F., Racagni G., Gennarelli M., et al., Long-Term duloxetine treatment normalizes altered brainderived neurotrophic factor expression in serotonin transporter knockout rats through the modulation of specific neurotrophin isoforms, Mol. Pharmacol., 2010, 77, 846–853 http://dx.doi.org/10.1124/mol.109.06308110.1124/mol.109.063081Search in Google Scholar

[177] Bozdagi O., Rich E., Tronel S., Sadahiro M., Patterson K., Shapiro M.L., et al., The neurotrophin-inducible gene VGF regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism, J. Neurosci., 2008, 28, 9857–9869 http://dx.doi.org/10.1523/JNEUROSCI.3145-08.200810.1523/JNEUROSCI.3145-08.2008Search in Google Scholar

[178] Lyford G.L., Yamagata K., Kaufmann W.E., Barnes C.A., Sanders L.K., Copeland N.G., et al., Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites, Neuron, 1995, 14, 433–445 http://dx.doi.org/10.1016/0896-6273(95)90299-610.1016/0896-6273(95)90299-6Search in Google Scholar

[179] Link W., Konietzko U., Kauselmann G., Krug M., Schwanke B., Frey U., et al., Somatodendritic expression of an immediate early gene is regulated by synaptic activity, Proc. Natl. Acad. Sci. USA, 1995, 92, 5734–5738 http://dx.doi.org/10.1073/pnas.92.12.573410.1073/pnas.92.12.5734Search in Google Scholar

[180] Pei Q., Zetterstrom T.S., Sprakes M., Tordera R., Sharp T., Antidepressant drug treatment induces Arc gene expression in the rat brain, Neuroscience, 2003, 121, 975–982 http://dx.doi.org/10.1016/S0306-4522(03)00504-910.1016/S0306-4522(03)00504-9Search in Google Scholar

[181] Molteni R., Calabrese F., Mancini M., Racagni G., Riva M.A., Basal and stress-induced modulation of activity-regulated cytoskeletal associated protein (Arc) in the rat brain following duloxetine treatment, Psychopharmacology (Berl.), 2008, 201, 285–292 http://dx.doi.org/10.1007/s00213-008-1276-710.1007/s00213-008-1276-7Search in Google Scholar PubMed

[182] Alme M.N., Wibrand K., Dagestad G., Bramham C.R., Chronic fluoxetine treatment induces brain region-specific upregulation of genes associated with BDNF-induced long-term potentiation, Neural Plast., 2007, 2007, 26496 http://dx.doi.org/10.1155/2007/2649610.1155/2007/26496Search in Google Scholar PubMed PubMed Central

[183] Larsen M.H., Olesen M., Woldbye D.P., Hay-Schmidt A., Hansen H.H., Ronn L.C., et al., Regulation of activity-regulated cytoskeleton protein (Arc) mRNA after acute and chronic electroconvulsive stimulation in the rat, Brain Res., 2005, 1064, 161–165 http://dx.doi.org/10.1016/j.brainres.2005.09.03910.1016/j.brainres.2005.09.039Search in Google Scholar PubMed

[184] Elizalde N., Pastor P.M., Garcia-Garcia A.L., Serres F., Venzala E., Huarte J., et al., Regulation of markers of synaptic function in mouse models of depression: chronic mild stress and decreased expression of VGLUT1, J. Neurochem., 2010, 114, 1302–1314 10.1111/j.1471-4159.2010.06854.xSearch in Google Scholar PubMed

[185] Covington H.E. 3rd, Lobo M.K., Maze I., Vialou V., Hyman J.M., Zaman S., et al., Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex, J. Neurosci., 2010, 30, 16082–16090 http://dx.doi.org/10.1523/JNEUROSCI.1731-10.201010.1523/JNEUROSCI.1731-10.2010Search in Google Scholar PubMed PubMed Central

[186] Molteni R., Calabrese F., Maj P.F., Olivier J.D., Racagni G., Ellenbroek B.A., et al., Altered expression and modulation of activity-regulated cytoskeletal associated protein (Arc) in serotonin transporter knockout rats, Eur. Neuropsychopharmacol., 2009, 19, 898–904 http://dx.doi.org/10.1016/j.euroneuro.2009.06.00810.1016/j.euroneuro.2009.06.008Search in Google Scholar PubMed

[187] Eriksson T.M., Delagrange P., Spedding M., Popoli M., Mathe A.A., Ogren S.O., et al., Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration, Mol. Psychiatr., 2012, 17, 173–184 http://dx.doi.org/10.1038/mp.2010.13110.1038/mp.2010.131Search in Google Scholar PubMed PubMed Central

[188] Ons S., Marti O., Armario A., Stress-induced activation of the immediate early gene Arc (activity-regulated cytoskeletonassociated protein) is restricted to telencephalic areas in the rat brain: relationship to c-fos mRNA, J. Neurochem., 2004, 89, 1111–1118 http://dx.doi.org/10.1111/j.1471-4159.2004.02396.x10.1111/j.1471-4159.2004.02396.xSearch in Google Scholar PubMed

[189] Mikkelsen J.D., Larsen M.H., Effects of stress and adrenalectomy on activity-regulated cytoskeleton protein (Arc) gene expression, Neurosci. Lett., 2006, 403, 239–243 http://dx.doi.org/10.1016/j.neulet.2006.04.04010.1016/j.neulet.2006.04.040Search in Google Scholar PubMed

[190] Fujino T., Leslie J.H., Eavri R., Chen J.L., Lin W.C., Flanders G.H., et al., CPG15 regulates synapse stability in the developing and adult brain, Genes Dev., 2011, 25, 2674–2685 http://dx.doi.org/10.1101/gad.176172.11110.1101/gad.176172.111Search in Google Scholar PubMed PubMed Central

[191] Son H., Banasr M., Choi M., Chae S.Y., Licznerski P., Lee B., et al., Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress, Proc. Natl. Acad. Sci. USA, 2012, 109, 11378–11383 http://dx.doi.org/10.1073/pnas.120119110910.1073/pnas.1201191109Search in Google Scholar PubMed PubMed Central

[192] Cunha C., Brambilla R., Thomas K.L., A simple role for BDNF in learning and memory?, Front. Mol. Neurosci., 2010, 3, 1 10.3389/neuro.02.001.2010Search in Google Scholar PubMed PubMed Central

[193] Li Z., Tan F., Thiele C.J., Inactivation of glycogen synthase kinase-3beta contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells, Mol. Cancer Ther., 2007, 6, 3113–3121 http://dx.doi.org/10.1158/1535-7163.MCT-07-013310.1158/1535-7163.MCT-07-0133Search in Google Scholar PubMed

[194] Blum R., Konnerth A., Neurotrophin-mediated rapid signaling in the central nervous system: mechanisms and functions, Physiology (Bethesda), 2005, 20, 70–78 http://dx.doi.org/10.1152/physiol.00042.200410.1152/physiol.00042.2004Search in Google Scholar PubMed

[195] Yoshii A., Constantine-Paton M., Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease, Dev. Neurobiol., 2010, 70, 304–322 10.1002/dneu.20765Search in Google Scholar PubMed PubMed Central