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5-HT2A Receptors and BDNF Regulation: Implications for Psychopathology

  • Minal Jaggar
  • Vidita A. Vaidya
Chapter
Part of the The Receptors book series (REC, volume 32)

Abstract

Serotonin2A (5-HT2A) receptors are implicated in the pathophysiology of mood disorders and schizophrenia, as well as in mediating the effects of hallucinogens. 5-HT2A receptors also serve as drug targets for specific classes of antidepressants and atypical antipsychotics. Preclinical and clinical studies have identified an important role for brain derived neurotrophic factor (BDNF) in the pathogenesis of depression and schizophrenia, and in the therapeutic actions of antidepressants and antipsychotics. 5-HT2A receptors have been reported to regulate BDNF expression within key limbic neurocircuits, including the prefrontal cortex and hippocampus. Further, alterations in BDNF directly impact 5-HT2A receptor expression, signaling and function. In this book chapter, we have extensively reviewed the current understanding of the regulation of BDNF by 5-HT2A receptors at multiple levels spanning from transcriptional regulation to modulation of BDNF signaling. We have also discussed the impact of perturbations in BDNF on 5-HT2A receptors, primarily focusing on studies from BDNF mouse mutant models. These studies highlight a reciprocal relationship between 5-HT2A receptors and BDNF, and suggest that such a crosstalk may play an important role in the actions of stress, antidepressant and atypical antipsychotic treatments, and in mediating hallucinogenic responses. We also highlight specific open questions hitherto unexplored in understanding the nature of interaction between 5-HT2A receptors and BDNF, and the implications of such a relationship to psychopathology.

Keywords

Serotonin Brain derived neurotrophic factor Tropomyosin related kinase B Neurotrophin Hippocampus Neocortex Stress DOI Ketanserin 

References

  1. 1.
    Artigas F (2013) Future directions for serotonin and antidepressants. ACS Chem Neurosci 4:5–8PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Duman RS, Monteggia LM (2006) A Neurotrophic model for stress-related mood disorders. Biol Psychiatry 59(12):1116–1127PubMedCrossRefGoogle Scholar
  3. 3.
    Guiard BP, Di Giovanni G (2015) Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link? Front Pharmacol 6:46PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Petit AC, Quesseveur G, Gressier F et al (2014) Converging translational evidence for the involvement of the serotonin 2A receptor gene in major depressive disorder. Prog Neuro-Psychopharmacology Biol Psychiatry 54:76–82CrossRefGoogle Scholar
  5. 5.
    Weisstaub NV, Zhou M, Lira A et al (2006) Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313:536–540PubMedCrossRefGoogle Scholar
  6. 6.
    Autry AE, Monteggia LM (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64:238–258PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Ebdrup BH, Rasmussen H, Arnt J, Glenthøj B (2011) Serotonin 2A receptor antagonists for treatment of schizophrenia. Expert Opin Investig Drugs 20:1211–1223PubMedCrossRefGoogle Scholar
  8. 8.
    Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76:99–125PubMedCrossRefGoogle Scholar
  9. 9.
    Chen A, Hough CJ, Li H (2003) Serotonin type II receptor activation facilitates synaptic plasticity via n-methyl-d-aspartate-mediated mechanism in the rat basolateral amygdala. Neuroscience 119:53–63PubMedCrossRefGoogle Scholar
  10. 10.
    Edelmann E, Lessmann V, Brigadski T (2014) Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity. Neuropharmacology 76:610–627PubMedCrossRefGoogle Scholar
  11. 11.
    Lesch K-P, Waider J (2012) Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron 76:175–191PubMedCrossRefGoogle Scholar
  12. 12.
    Banasr M, Hery M, Printemps R, Daszuta A (2004) Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29:450–460PubMedCrossRefGoogle Scholar
  13. 13.
    Jha S, Rajendran R, Fernandes KA, Vaidya VA (2008) 5-HT2A/2C receptor blockade regulates progenitor cell proliferation in the adult rat hippocampus. Neurosci Lett 441:210–214PubMedCrossRefGoogle Scholar
  14. 14.
    Klempin F, Babu H, De Pietri Tonelli D et al (2010) Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. Front Mol Neurosci 3Google Scholar
  15. 15.
    Sairanen M, Lucas G, Ernfors P et al (2005) 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 25:1089–1094PubMedCrossRefGoogle Scholar
  16. 16.
    Waterhouse EG, An JJ, Orefice LL et al (2012) BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission. J Neurosci 32:14318–14330PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Bekinschtein P, Renner MC, Gonzalez MC, Weisstaub N (2013) Role of medial prefrontal cortex serotonin 2A receptors in the control of retrieval of recognition memory in rats. J Neurosci 33:15716–15725PubMedCrossRefGoogle Scholar
  18. 18.
    Lu B, Nagappan G, Lu Y (2014) BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol 220:223–250PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang G, Ásgeirsdóttir HN, Cohen SJ et al (2013) Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Neuropharmacology 64:403–413PubMedCrossRefGoogle Scholar
  20. 20.
    Martinowich K, Manji H, Lu B (2007) New insights into BDNF function in depression and anxiety. Nat Neurosci 10:1089–1093PubMedCrossRefGoogle Scholar
  21. 21.
    Geyer MA, Vollenweider FX (2008) Serotonin research: contributions to understanding psychoses. Trends Pharmacol Sci 29:445–453PubMedCrossRefGoogle Scholar
  22. 22.
    Lu B, Martinowich K (2008) Cell biology of BDNF and its relevance to schizophrenia. Novartis Found Symp 289:119–129PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Meltzer HY, Massey BW, Horiguchi M (2012) Serotonin receptors as targets for drugs useful to treat psychosis and cognitive impairment in schizophrenia. Curr Pharm Biotechnol 13:1572–1586PubMedCrossRefGoogle Scholar
  24. 24.
    Mestre TA, Zurowski M, Fox SH (2013) 5-Hydroxytryptamine 2A receptor antagonists as potential treatment for psychiatric disorders. Expert Opin Investig Drugs 22:411–421PubMedCrossRefGoogle Scholar
  25. 25.
    Notaras M, Hill R, van den Buuse M (2015a) A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci Biobehav Rev 51:15–30PubMedCrossRefGoogle Scholar
  26. 26.
    Daftary SS, Calderon G, Rios M (2012) Essential role of brain-derived neurotrophic factor in the regulation of serotonin transmission in the basolateral amygdala. Neuroscience 224:125–134PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Homberg JR, Molteni R, Calabrese F, M a R (2014) The serotonin-BDNF duo: developmental implications for the vulnerability to psychopathology. Neurosci Biobehav Rev 43:35–47PubMedCrossRefGoogle Scholar
  28. 28.
    Klein AB, Santini MA, Aznar S et al (2010b) Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice. Neuroscience 169:1007–1016PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Martinowich K, Lu B (2008) Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 33:73–83PubMedCrossRefGoogle Scholar
  30. 30.
    Mattson MP, Maudsley S, Martin B (2004) BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci 27:589–594PubMedCrossRefGoogle Scholar
  31. 31.
    Trajkovska V, Santini M a., Marcussen a. B, et al (2009) BDNF downregulates 5-HT2A receptor protein levels in hippocampal cultures. Neurochem Int 55:697–702Google Scholar
  32. 32.
    Vaidya VA, Marek GJ, Aghajanian GK, Duman RS (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci 17:2785–2795PubMedGoogle Scholar
  33. 33.
    Vaidya VA, Terwilliger R, Duman R (1999) Role of 5-HT 2A receptors in the stress-induced down-regulation of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett 262:1–4PubMedCrossRefGoogle Scholar
  34. 34.
    Turlejski K (1996) Evolutionary ancient roles of serotonin: long-lasting regulation of activity and development. Acta Neurobiol Exp (Wars) 56:619–636Google Scholar
  35. 35.
    Weiger WA (1997) Serotonergic modulation of behaviour: a phylogenetic overview. Biol Rev Camb Philos Soc 72:61–95PubMedCrossRefGoogle Scholar
  36. 36.
    Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38:1083–1152PubMedCrossRefGoogle Scholar
  37. 37.
    Adlersberg M, Arango V, Hsiung S et al (2000) In vitro autoradiography of serotonin 5-HT2A/2C receptor-activated G protein: Guanosine-5′-(g-[ 35S])thiotriphosphate binding in rat brain. J Neurosci Res 61:674–685PubMedCrossRefGoogle Scholar
  38. 38.
    Millan MJ, Marin P, Bockaert J, Mannoury la Cour C (2008) Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol Sci 29:454–464PubMedCrossRefGoogle Scholar
  39. 39.
    Bohn LM, Schmid CL (2010) Serotonin receptor signaling and regulation via β-arrestins. Crit Rev Biochem Mol Biol 45:555–566PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Schmid CL, Bohn LM (2010) Serotonin , but not N-Methyltryptamines , activates the serotonin 2A receptor via a β-Arrestin2 / Src / Akt Signaling complex in vivo. Drugs 30:13513–13524Google Scholar
  41. 41.
    González-Maeso J, Weisstaub NV, Zhou M et al (2007) Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53:439–452PubMedCrossRefGoogle Scholar
  42. 42.
    Albizu L, Holloway T, González-Maeso J, Sealfon SC (2011) Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors. Neuropharmacology 61:770–777PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Delille HK, Becker JM, Burkhardt S et al (2012) Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. Neuropharmacology 62:2184–2191PubMedCrossRefGoogle Scholar
  44. 44.
    Fribourg M, Moreno JL, Holloway T et al (2011) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell 147:1011–1023PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Moreno JL, Miranda-Azpiazu P, García-Bea A et al (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal 9:ra5.  https://doi.org/10.1126/scisignal.aab0467 PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Borroto-Escuela DO, Romero-Fernandez W, Narvaez M et al (2014) Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes. Biochem Biophys Res Commun 443:278–284PubMedCrossRefGoogle Scholar
  47. 47.
    Bhattacharyya S, Puri S, Miledi R, Panicker MM (2002) Internalization and recycling of 5-HT2A receptors activated by serotonin and protein kinase C-mediated mechanisms. Proc Natl Acad Sci U S A 99:14470–14475PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Raote I, Bhattacharyya S, Panicker MM (2013) Functional selectivity in serotonin receptor 2A (5-HT2A) endocytosis, recycling, and phosphorylation. Mol Pharmacol 83:42–50PubMedCrossRefGoogle Scholar
  49. 49.
    Aghajanian GK, Marek GJ (1999) Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825:161–171PubMedCrossRefGoogle Scholar
  50. 50.
    Andrade R (2011) Serotonergic regulation of neuronal excitability in the prefrontal cortex. Neuropharmacology 61:382–386PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Martín-Ruiz R, Puig MV, Celada P et al (2001) Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci 21:9856–9866PubMedGoogle Scholar
  52. 52.
    Day M, Olson PA, Platzer J et al (2002) Stimulation of 5-HT(2) receptors in prefrontal pyramidal neurons inhibits Ca(v)1.2 L type Ca(2+) currents via a PLCbeta/IP3/calcineurin signaling cascade. J Neurophysiol 87:2490–2504PubMedCrossRefGoogle Scholar
  53. 53.
    Villalobos C, Foehring RC, Lee JC, Andrade R (2011) Essential role for phosphatidylinositol 4,5-Bisphosphate in the expression, regulation, and gating of the slow Afterhyperpolarization current in the cerebral cortex. J Neurosci 31:18303–18312PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Gresch PJ, Barrett RJ, Sanders-Bush E, Smith RL (2007) 5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide. J Pharmacol Exp Ther 320:662–669PubMedCrossRefGoogle Scholar
  55. 55.
    Quesseveur G, Nguyen HT, Gardier AM, Guiard BP (2012) 5-HT2A ligands in the treatment of anxiety and depression. Expert Opin Investig Drugs 21:1701–1725PubMedCrossRefGoogle Scholar
  56. 56.
    Yadav PN, Kroeze WK, Farrell MS, Roth BL (2011) Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo. J Pharmacol Exp Ther 339:99–105PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Watanabe N, Omori IM, Nakagawa A, et al (2011) Mirtazapine versus other antidepressive agents for depression. Cochrane database Syst Rev. CD006528
  58. 58.
    Gray JA, Roth BL (2007) Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr Bull 33:1100–1119PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Ul Haq R, Anderson ML, Hollnagel J-O et al (2015) Serotonin dependent masking of hippocampal sharp wave ripples. Neuropharmacology 101:188–203PubMedCrossRefGoogle Scholar
  60. 60.
    van Wel JHP, Kuypers KPC, Theunissen EL et al (2011) Blockade of 5-HT2 receptor selectively prevents MDMA-induced verbal memory impairment. Neuropsychopharmacology 36:1932–1939PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Mengod G, Vilaró MT, Raurich A et al (1996) 5-HT receptors in mammalian brain: receptor autoradiography and in situ hybridization studies of new ligands and newly identified receptors. Histochem J 28:747–758PubMedCrossRefGoogle Scholar
  62. 62.
    Mengod G, Palacios JM, Cortes R (2015) Cartography of 5-HT1A and 5-HT2A receptor subtypes in prefrontal cortex and its projections. ACS Chem Neurosci 6:1089–1098PubMedCrossRefGoogle Scholar
  63. 63.
    Willins DL, Deutch AY, Roth BL (1997) Serotonin 5-HT2A receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27:79–82PubMedCrossRefGoogle Scholar
  64. 64.
    Ettrup A, da Cunha-Bang S, McMahon B et al (2014) Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36. J Cereb Blood Flow Metab 34:1188–1196PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Tanaka KF, Samuels BA, Hen R (2012) Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus. Philos Trans R Soc B Biol Sci 367:2395–2401CrossRefGoogle Scholar
  66. 66.
    Szabo ST, Blier P (2001) Functional and pharmacological characterization of the modulatory role of serotonin on the firing activity of locus coeruleus norepinephrine neurons. Brain Res 922:9–20PubMedCrossRefGoogle Scholar
  67. 67.
    Boothman LJ, Sharp T (2005) A role for midbrain raphe gamma aminobutyric acid neurons in 5-hydroxytryptamine feedback control. Neuroreport 16:891–896PubMedCrossRefGoogle Scholar
  68. 68.
    Puig MV, Celada P, Díaz-Mataix L, Artigas F (2003) In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5-HT2A receptors: relationship to thalamocortical afferents. Cereb Cortex 13:870–882PubMedCrossRefGoogle Scholar
  69. 69.
    Marek GJ, Aghajanian GK (1996) LSD and the phenethylamine hallucinogen DOI are potent partial agonists at 5-HT2A receptors on interneurons in rat piriform cortex. J Pharmacol Exp Ther 278:1373–1382PubMedGoogle Scholar
  70. 70.
    Marek GJ, Aghajanian GK (1994) Excitation of interneurons in piriform cortex by 5-hydroxytryptamine: blockade by MDL 100,907, a highly selective 5-HT2A receptor antagonist. Eur J Pharmacol 259:137–141PubMedCrossRefGoogle Scholar
  71. 71.
    Narla C, Dunn HA, Ferguson SSG, Poulter MO (2015) Suppression of piriform cortex activity in rat by corticotropin-releasing factor 1 and serotonin 2A/C receptors. Front Cell Neurosci 9:200PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Sheldon PW, Aghajanian GK (1990) Serotonin (5-HT) induces IPSPs in pyramidal layer cells of rat piriform cortex: evidence for the involvement of a 5-HT2-activated interneuron. Brain Res 506:62–69PubMedCrossRefGoogle Scholar
  73. 73.
    Shen RY, Andrade R (1998) 5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus. J Pharmacol Exp Ther 285:805–812PubMedGoogle Scholar
  74. 74.
    Sheldon PW, Aghajanian GK (1991) Excitatory responses to serotonin (5-HT) in neurons of the rat piriform cortex: evidence for mediation by 5-HT1C receptors in pyramidal cells and 5-HT2 receptors in interneurons. Synapse 9:208–218PubMedCrossRefGoogle Scholar
  75. 75.
    Hamada S, Senzaki K, Hamaguchi-Hamada K et al (1998) Localization of 5-HT2A receptor in rat cerebral cortex and olfactory system revealed by immunohistochemistry using two antibodies raised in rabbit and chicken. Mol Brain Res 54:199–211PubMedCrossRefGoogle Scholar
  76. 76.
    Hirst WD, Price GW, Rattray M, Wilkin GP (1998) Serotonin transporters in adult rat brain astrocytes revealed by [3H]5-HT uptake into glial plasmalemmal vesicles. Neurochem Int 33:11–22PubMedCrossRefGoogle Scholar
  77. 77.
    Meller R, Harrison PJ, Elliott JM, Sharp T (2002b) In vitro evidence that 5-hydroxytryptamine increases efflux of glial glutamate via 5-HT(2A) receptor activation. J Neurosci Res 67:399–405PubMedCrossRefGoogle Scholar
  78. 78.
    Hagberg GB, Blomstrand F, Nilsson M et al (1998) Stimulation of 5-HT2A receptors on astrocytes in primary culture opens voltage-independent Ca2+ channels. Neurochem Int 32:153–162PubMedCrossRefGoogle Scholar
  79. 79.
    Jalonen TO, Margraf RR, Wielt DB et al (1997) Serotonin induces inward potassium and calcium currents in rat cortical astrocytes. Brain Res 758:69–82PubMedCrossRefGoogle Scholar
  80. 80.
    Glebov K, Löchner M, Jabs R et al (2015) Serotonin stimulates secretion of exosomes from microglia cells. Glia 63:626–634PubMedCrossRefGoogle Scholar
  81. 81.
    Béïque J-C, Imad M, Mladenovic L et al (2007) Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci U S A 104:9870–9875PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Marinova Z, Monoranu C-M, Fetz S et al (2015) Region-specific regulation of the serotonin 2A receptor expression in development and ageing in post mortem human brain. Neuropathol Appl Neurobiol 41:520–532PubMedCrossRefGoogle Scholar
  83. 83.
    Zhang Z-W (2003) Serotonin induces tonic firing in layer V pyramidal neurons of rat prefrontal cortex during postnatal development. J Neurosci 23:3373–3384PubMedGoogle Scholar
  84. 84.
    Zhang L, Ma W, Barker J, Rubinow D (1999) Sex differences in expression of serotonin receptors (subtypes 1A and 2A) in rat brain: a possible role of testosterone. Neuroscience 94:251–259PubMedCrossRefGoogle Scholar
  85. 85.
    Chen M, Russo-Neustadt A (2013) Kinetics of norepinephrine- and serotonin-induced BDNF release in cultured embryonic hippocampal neurons. Neurosci & Med 04:194–207Google Scholar
  86. 86.
    Meller R, Babity J, Grahame-Smith D (2002a) 5-HT 2A receptor activation leads to increased BDNF mRNA expression in C6 glioma cells. NeuroMolecular Med 1:197–205PubMedCrossRefGoogle Scholar
  87. 87.
    Conner JM, Lauterborn JC, Yan Q et al (1997) Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci 17:2295–2313PubMedGoogle Scholar
  88. 88.
    Kawamoto Y, Nakamura S, Nakano S et al (1996) Immunohistochemical localization of brain-derived neurotrophic factor in adult rat brain. Neuroscience 74:1209–1226PubMedCrossRefGoogle Scholar
  89. 89.
    Lewin GR, Barde Y-A (1996) Physiology of the Neurotrophins. Annu Rev Neurosci 19:289–317PubMedCrossRefGoogle Scholar
  90. 90.
    Yan Q, Rosenfeld R, Matheson C et al (1997) Expression of brain-derived neurotrophic factor protein in the adult rat central nervous system. Neuroscience 78:431–448PubMedCrossRefGoogle Scholar
  91. 91.
    Benraiss A, Chmielnicki E, Lerner K et al (2001) Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J Neurosci 21:6718–6731PubMedGoogle Scholar
  92. 92.
    Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (2001) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21:6706–6717PubMedGoogle Scholar
  93. 93.
    Scharfman H, Goodman J, Macleod A et al (2005) Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol 192:348–356PubMedCrossRefGoogle Scholar
  94. 94.
    Lipsky RH, Marini AM (2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci 1122:130–143PubMedCrossRefGoogle Scholar
  95. 95.
    Barnabé-Heider F, Miller FD (2003) Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. J Neurosci 23:5149–5160PubMedGoogle Scholar
  96. 96.
    Barde YA, Edgar D, Thoenen H (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J 1:549–553PubMedPubMedCentralGoogle Scholar
  97. 97.
    Bergami M, Rimondini R, Santi S et al (2008a) Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety-like behavior. Proc Natl Acad Sci U S A 105:15570–15575PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Causing CG, Gloster A, Aloyz R et al (1997) Synaptic innervation density is regulated by neuron-derived BDNF. Neuron 18:257–267PubMedCrossRefGoogle Scholar
  99. 99.
    Lu B (2003) Pro-region of neurotrophins: role in synaptic modulation. Neuron 39:735–738PubMedCrossRefGoogle Scholar
  100. 100.
    Seidah NG, Benjannet S, Pareek S et al (1996) Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 379:247–250PubMedCrossRefGoogle Scholar
  101. 101.
    Yang F, Je H-S, Ji Y et al (2009) Pro-BDNF-induced synaptic depression and retraction at developing neuromuscular synapses. J Cell Biol 185:727–741PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Bergami M, Santi S, Formaggio E et al (2008b) Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes. J Cell Biol 183:213–221PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309PubMedCrossRefGoogle Scholar
  104. 104.
    Fayard B, Loeffler S, Weis J et al (2005) The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR but not to TrkA or TrkC. J Neurosci Res 80:18–28PubMedCrossRefGoogle Scholar
  105. 105.
    Koshimizu H, Hazama S, Hara T et al (2010) Distinct signaling pathways of precursor BDNF and mature BDNF in cultured cerebellar granule neurons. Neurosci Lett 473:229–232PubMedCrossRefGoogle Scholar
  106. 106.
    Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond Ser B Biol Sci 361:1545–1564CrossRefGoogle Scholar
  107. 107.
    Taylor AR, Gifondorwa DJ, Robinson MB et al (2012) Motoneuron programmed cell death in response to proBDNF. Dev Neurobiol 72:699–712PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Teng HK, Teng KK, Lee R et al (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25:5455–5463PubMedCrossRefGoogle Scholar
  109. 109.
    Adachi N, Kohara K, Tsumoto T (2005) Difference in trafficking of brain-derived neurotrophic factor between axons and dendrites of cortical neurons, revealed by live-cell imaging. BMC Neurosci 6:42PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Jovanovic JN, Czernik AJ, Fienberg AA et al (2000) Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci 3:323–329PubMedCrossRefGoogle Scholar
  111. 111.
    Kovalchuk Y, Hanse E, Kafitz KW, Konnerth A (2002) Postsynaptic induction of BDNF-mediated long-term potentiation. Science 295:1729–1734PubMedCrossRefGoogle Scholar
  112. 112.
    Fryer RH, Kaplan DR, Kromer LF (1997) Truncated trkB receptors on nonneuronal cells inhibit BDNF-induced neurite outgrowth in vitro. Exp Neurol 148:616–627PubMedCrossRefGoogle Scholar
  113. 113.
    Strohmaier C, Carter BD, Urfer R et al (1996) A splice variant of the neurotrophin receptor trkB with increased specificity for brain-derived neurotrophic factor. EMBO J 15:3332–3337PubMedPubMedCentralGoogle Scholar
  114. 114.
    Friedman WJ, Black IB, Kaplan DR (1998) Distribution of the neurotrophins brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 in the postnatal rat brain: an immunocytochemical study. Neuroscience 84:101–114PubMedCrossRefGoogle Scholar
  115. 115.
    Maisonpierre PC, Belluscio L, Friedman B et al (1990) NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression. Neuron 5:501–509PubMedCrossRefGoogle Scholar
  116. 116.
    Kim J, Yang M, Kim J et al (2014) Developmental and degenerative modulation of brain-derived neurotrophic factor transcript variants in the mouse hippocampus. Int J Dev Neurosci 38:68–73PubMedCrossRefGoogle Scholar
  117. 117.
    Menshanov PN, Lanshakov DA, Dygalo NN (2015) proBDNF is a major product of bdnf gene expressed in the perinatal rat cortex. Physiol Res 64(6):925–934PubMedGoogle Scholar
  118. 118.
    Zafra F, Hengerer B, Leibrock J et al (1990) Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J 9:3545–3550PubMedPubMedCentralGoogle Scholar
  119. 119.
    Aid T, Kazantseva A, Piirsoo M et al (2007) Mouse and ratBDNF gene structure and expression revisited. J Neurosci Res 85:525–535PubMedCrossRefGoogle Scholar
  120. 120.
    Sathanoori M, Dias BG, Nair AR et al (2004) Differential regulation of multiple brain-derived neurotrophic factor transcripts in the postnatal and adult rat hippocampus during development, and in response to kainate administration. Mol Brain Res 130:170–177PubMedCrossRefGoogle Scholar
  121. 121.
    Liu Q-R, Walther D, Drgon T et al (2005) Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson’s disease. Am J Med Genet B Neuropsychiatr Genet 134B:93–103PubMedCrossRefGoogle Scholar
  122. 122.
    An JJ, Gharami K, Liao G-Y et al (2008) Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134:175–187PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Baj G, Leone E, Chao MV, Tongiorgi E (2011) Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments. Proc Natl Acad Sci U S A 108:16813–16818PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Metsis M, Timmusk T, Arenas E, Persson H (1993) Differential usage of multiple brain-derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc Natl Acad Sci U S A 90:8802–8806PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Pruunsild P, Kazantseva A, Aid T et al (2007) Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics 90:397–406PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Timmusk T, Belluardo N, Persson H, Metsis M (1994a) Developmental regulation of brain-derived neurotrophic factor messenger RNAs transcribed from different promoters in the rat brain. Neuroscience 60:287–291PubMedCrossRefGoogle Scholar
  127. 127.
    Timmusk T, Lendahl U, Funakoshi H et al (1995) Identification of brain-derived neurotrophic factor promoter regions mediating tissue-specific, axotomy-, and neuronal activity-induced expression in transgenic mice. J Cell Biol 128:185–199PubMedCrossRefGoogle Scholar
  128. 128.
    Timmusk T, Persson H, Metsis M (1994b) Analysis of transcriptional initiation and translatability of brain-derived neurotrophic factor mRNAs in the rat brain. Neurosci Lett 177:27–31PubMedCrossRefGoogle Scholar
  129. 129.
    Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1768–1777PubMedGoogle Scholar
  130. 130.
    Tsankova NM, Berton O, Renthal W et al (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525PubMedCrossRefGoogle Scholar
  131. 131.
    Bekinschtein P, Oomen CA, Saksida LM, Bussey TJ (2011) Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable? Semin Cell Dev Biol 22:536–542PubMedCrossRefGoogle Scholar
  132. 132.
    Falkenberg T, Mohammed AK, Henriksson B et al (1992) Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neurosci Lett 138:153–156PubMedCrossRefGoogle Scholar
  133. 133.
    Hall J, Thomas KL, Everitt BJ (2000) Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci 3:533–535PubMedCrossRefGoogle Scholar
  134. 134.
    Radecki DT, Brown LM, Martinez J, Teyler TJ (2005) BDNF protects against stress-induced impairments in spatial learning and memory and LTP. Hippocampus 15:246–253PubMedCrossRefGoogle Scholar
  135. 135.
    Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547PubMedGoogle Scholar
  136. 136.
    Casarotto PC, dos Santos PC, Lucas GA et al (2015) BDNF-TRKB signaling system of the dorsal periaqueductal gray matter is implicated in the panicolytic-like effect of antidepressant drugs. Eur Neuropsychopharmacol 25:913–922PubMedCrossRefGoogle Scholar
  137. 137.
    Licata SC, Shinday NM, Huizenga MN et al (2013) Alterations in brain-derived neurotrophic factor in the mouse hippocampus following acute but not repeated benzodiazepine treatment. PLoS One 8:e84806PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Bai O, Chlan-Fourney J, Bowen R et al (2003) Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs. J Neurosci Res 71:127–131PubMedCrossRefGoogle Scholar
  139. 139.
    Chlan-Fourney J, Ashe P, Nylen K et al (2002) Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration. Brain Res 954:11–20PubMedCrossRefGoogle Scholar
  140. 140.
    Braun AA, Herring NR, Schaefer TL et al (2011) Neurotoxic (+)-methamphetamine treatment in rats increases brain-derived neurotrophic factor and tropomyosin receptor kinase B expression in multiple brain regions. Neuroscience 184:164–171PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Schmidt HD, Sangrey GR, Darnell SB et al (2012) Increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area during cocaine abstinence is associated with increased histone acetylation at BDNF exon I-containing promoters. J Neurochem 120:202–209PubMedCrossRefGoogle Scholar
  142. 142.
    Butovsky E, Juknat A, Goncharov I et al (2005) In vivo up-regulation of brain-derived neurotrophic factor in specific brain areas by chronic exposure to Delta-tetrahydrocannabinol. J Neurochem 93:802–811PubMedCrossRefGoogle Scholar
  143. 143.
    Martin DA, Marona-Lewicka D, Nichols DE, Nichols CD (2014) Chronic LSD alters gene expression profiles in the mPFC relevant to schizophrenia. Neuropharmacology 83:1–8PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Caputo V, Sinibaldi L, Fiorentino A et al (2011) Brain derived neurotrophic factor (BDNF) expression is regulated by microRNAs miR-26a and miR-26b allele-specific binding. PLoS One 6:e28656PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Fukuchi M, Tsuda M (2010) Involvement of the 3′-untranslated region of the brain-derived neurotrophic factor gene in activity-dependent mRNA stabilization. J Neurochem 115:1222–1233PubMedCrossRefGoogle Scholar
  146. 146.
    Hwang JJ, Park M-H, Choi S-Y, Koh J-Y (2005) Activation of the Trk signaling pathway by extracellular zinc. Role of metalloproteinases. J Biol Chem 280:11995–12001PubMedCrossRefGoogle Scholar
  147. 147.
    Oe S, Yoneda Y (2010) Cytoplasmic polyadenylation element-like sequences are involved in dendritic targeting of BDNF mRNA in hippocampal neurons. FEBS Lett 584:3424–3430PubMedCrossRefGoogle Scholar
  148. 148.
    Wu YC, Williamson R, Li Z et al (2011) Dendritic trafficking of brain-derived neurotrophic factor mRNA: regulation by translin-dependent and -independent mechanisms. J Neurochem 116:1112–1121PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Evans SF, Irmady K, Ostrow K et al (2011) Neuronal brain-derived neurotrophic factor is synthesized in excess, with levels regulated by sortilin-mediated trafficking and lysosomal degradation. J Biol Chem 286:29556–29567PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Wong Y-H, Lee C-M, Xie W et al (2015) Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin. Proc Natl Acad Sci U S A 112:E4475–E4484PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Rohe M, Hartl D, Fjorback AN et al (2013) SORLA-mediated trafficking of TrkB enhances the response of neurons to BDNF. PLoS One 8:e72164PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Eide FF, Vining ER, Eide BL et al (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 16:3123–3129PubMedPubMedCentralGoogle Scholar
  153. 153.
    Fenner BM (2012) Truncated TrkB: beyond a dominant negative receptor. Cytokine Growth Factor Rev 23:15–24PubMedCrossRefGoogle Scholar
  154. 154.
    Fryer RH, Kaplan DR, Feinstein SC et al (1996) Developmental and mature expression of full-length and truncated TrkB receptors in the rat forebrain. J Comp Neurol 374:21–40PubMedCrossRefGoogle Scholar
  155. 155.
    Coppell A, Pei Q, Zetterström TS (2003) Bi-phasic change in BDNF gene expression following antidepressant drug treatment. Neuropharmacology 44:903–910PubMedCrossRefGoogle Scholar
  156. 156.
    Ivy a S, Rodriguez FG, Garcia C et al (2003) Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacol Biochem Behav 75:81–88PubMedCrossRefGoogle Scholar
  157. 157.
    De Foubert G, Carney SL, Robinson CS et al (2004) Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment. Neuroscience 128:597–604PubMedCrossRefGoogle Scholar
  158. 158.
    Donnici L, Tiraboschi E, Tardito D et al (2008) Time-dependent biphasic modulation of human BDNF by antidepressants in neuroblastoma cells. BMC Neurosci 9:61PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Khundakar AA, Zetterström TSC (2006) Biphasic change in BDNF gene expression following antidepressant drug treatment explained by differential transcript regulation. Brain Res 1106:12–20PubMedCrossRefGoogle Scholar
  160. 160.
    Zetterström TSC, Pei Q, Madhav TR et al (1999) Manipulations of brain 5-HT levels affect gene expression for BDNF in rat brain. Neuropharmacology 38:1063–1073PubMedCrossRefGoogle Scholar
  161. 161.
    Balu DT, Hoshaw BA, Malberg JE et al (2008) Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res 1211:37–43PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Mannari C, Origlia N, Scatena A et al (2008) BDNF level in the rat prefrontal cortex increases following chronic but not acute treatment with duloxetine, a dual acting inhibitor of noradrenaline and serotonin re-uptake. Cell Mol Neurobiol 28:457–468PubMedCrossRefGoogle Scholar
  163. 163.
    Zetterström TSC, A a C, A a K (2014) The role of 5-hydroxytryptamine receptor subtypes in the regulation of brain-derived neurotrophic factor gene expression. J Pharm Pharmacol 66:53–61PubMedCrossRefGoogle Scholar
  164. 164.
    Pilar-Cuéllar F, Vidal R, Pazos a (2012) Subchronic treatment with fluoxetine and ketanserin increases hippocampal brain-derived neurotrophic factor, β-catenin and antidepressant-like effects. Br J Pharmacol 165:1046–1057Google Scholar
  165. 165.
    Musazzi L, Rimland JM, Ieraci a, et al (2014) Pharmacological characterization of BDNF promoters I, II and IV reveals that serotonin and norepinephrine input is sufficient for transcription activation. Int J Neuropsychopharmacol 17:779–791Google Scholar
  166. 166.
    Lauterborn JC, Rivera S, Stinis CT et al (1996) Differential effects of protein synthesis inhibition on the activity-dependent expression of BDNF transcripts: evidence for immediate-early gene responses from specific promoters. J Neurosci 16:7428–7436PubMedGoogle Scholar
  167. 167.
    Nair A, Vadodaria KC, Banerjee SB et al (2007) Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus. Neuropsychopharmacology 32:1504–1519PubMedCrossRefGoogle Scholar
  168. 168.
    Dias BG, Banerjee SB, Duman RS, V a V (2003) Differential regulation of brain derived neurotrophic factor transcripts by antidepressant treatments in the adult rat brain. Neuropharmacology 45:553–563PubMedCrossRefGoogle Scholar
  169. 169.
    Russo-Neustadt A, Beard R, Huang Y, Cotman C (2000) Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 101:305–312PubMedCrossRefGoogle Scholar
  170. 170.
    Lubin FD, Roth TL, Sweatt JD (2008) Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci 28:10576–10586PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Zheng F, Zhou X, Moon C, Wang H (2012) Regulation of brain-derived neurotrophic factor expression in neurons. Int J Physiol Pathophysiol Pharmacol 4:188–200PubMedPubMedCentralGoogle Scholar
  172. 172.
    Cavus I, Duman RS (2003) Influence of estradiol, stress, and 5-HT2A agonist treatment on brain-derived neurotrophic factor expression in female rats. Biol Psychiatry 54:59–69PubMedCrossRefGoogle Scholar
  173. 173.
    Vaidya VA, Castro ME, Pei Q et al (2001) Influence of thyroid hormone on 5-HT1A and 5-HT2A receptor-mediated regulation of hippocampal BDNF mRNA expression. Neuropharmacology 40:48–56PubMedCrossRefGoogle Scholar
  174. 174.
    Morita K, Her S (2008) Progesterone Pretreatment enhances serotonin-stimulated BDNF gene expression in rat C6 Glioma cells through production of 5α-reduced Neurosteroids. J Mol Neurosci 34:193–200PubMedCrossRefGoogle Scholar
  175. 175.
    Gewirtz JC, Chen AC, Terwilliger R et al (2002) Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. Pharmacol Biochem Behav 73:317–326PubMedCrossRefGoogle Scholar
  176. 176.
    Bombardi C (2012) Neuronal localization of 5-HT2A receptor immunoreactivity in the rat hippocampal region. Brain Res Bull 87:259–273PubMedCrossRefGoogle Scholar
  177. 177.
    Piguet P, Galvan M (1994) Transient and long-lasting actions of 5-HT on rat dentate gyrus neurones in vitro. J Physiol 481(Pt 3):629–639PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Hayes VY, Towner MD, Isackson PJ (1997) Organization, sequence and functional analysis of a mouse BDNF promoter. Brain Res Mol Brain Res 45:189–198PubMedCrossRefGoogle Scholar
  179. 179.
    Tabuchi A, Sakaya H, Kisukeda T et al (2002) Involvement of an upstream stimulatory factor as well as cAMP-responsive element-binding protein in the activation of brain-derived neurotrophic factor gene promoter I. J Biol Chem 277:35920–35931PubMedCrossRefGoogle Scholar
  180. 180.
    Gao X, Daugherty RL, Tourtellotte WG (2007) Regulation of low affinity neurotrophin receptor (p75(NTR)) by early growth response (Egr) transcriptional regulators. Mol Cell Neurosci 36:501–514PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Chen A, Xiong L-J, Tong Y, Mao M (2013) Neuroprotective effect of brain-derived neurotrophic factor mediated by autophagy through the PI3K/Akt/mTOR pathway. Mol Med Rep 8:1011–1016PubMedCrossRefGoogle Scholar
  182. 182.
    Lee FS, Rajagopal R, Chao MV (2002) Distinctive features of Trk neurotrophin receptor transactivation by G protein-coupled receptors. Cytokine Growth Factor Rev 13:11–17PubMedCrossRefGoogle Scholar
  183. 183.
    Rajagopal R, Chen Z-Y, Lee FS, Chao MV (2004) Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes. J Neurosci 24:6650–6658PubMedCrossRefGoogle Scholar
  184. 184.
    Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948PubMedCrossRefGoogle Scholar
  185. 185.
    Shum JKS, Melendez JA, Jeffrey JJ (2002) Serotonin-induced MMP-13 production is mediated via phospholipase C, protein kinase C, and ERK1/2 in rat uterine smooth muscle cells. J Biol Chem 277:42830–42840PubMedCrossRefGoogle Scholar
  186. 186.
    Yabanoglu S, Akkiki M, Seguelas M-H et al (2009) Platelet derived serotonin drives the activation of rat cardiac fibroblasts by 5-HT2A receptors. J Mol Cell Cardiol 46:518–525PubMedCrossRefGoogle Scholar
  187. 187.
    Baxter GT, Radeke MJ, Kuo RC et al (1997) Signal transduction mediated by the truncated trkB receptor isoforms, trkB.T1 and trkB.T2. J Neurosci 17:2683–2690PubMedGoogle Scholar
  188. 188.
    Michaelsen K, Zagrebelsky M, Berndt-Huch J et al (2010) Neurotrophin receptors TrkB.T1 and p75NTR cooperate in modulating both functional and structural plasticity in mature hippocampal neurons. Eur J Neurosci 32:1854–1865PubMedCrossRefGoogle Scholar
  189. 189.
    Rose CR, Blum R, Pichler B et al (2003) Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426:74–78PubMedCrossRefGoogle Scholar
  190. 190.
    Sherrard RM, Dixon KJ, Bakouche J et al (2009) Differential expression of TrkB isoforms switches climbing fiber-Purkinje cell synaptogenesis to selective synapse elimination. Dev Neurobiol 69:647–662PubMedCrossRefGoogle Scholar
  191. 191.
    Jang S-W, Liu X, Pradoldej S et al (2010) N-acetylserotonin activates TrkB receptor in a circadian rhythm. Proc Natl Acad Sci U S A 107:3876–3881PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Kruk JS, Vasefi MS, Heikkila JJ, Beazely MA (2013) Reactive oxygen species are required for 5-HT-induced transactivation of neuronal platelet-derived growth factor and TrkB receptors, but not for ERK1/2 activation. PLoS One 8:e77027PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Overland AC, Insel PA (2015) Heterotrimeric G proteins directly regulate MMP14/membrane type-1 matrix metalloprotease: a novel mechanism for GPCR-EGFR transactivation. J Biol Chem 290:9941–9947PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Cattaneo F, Guerra G, Parisi M et al (2014) Cell-surface receptors transactivation mediated by g protein-coupled receptors. Int J Mol Sci 15:19700–19728PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Kamato D, Rostam MA, Bernard R et al (2015) The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier. Cell Mol Life Sci 72:799–808PubMedCrossRefGoogle Scholar
  196. 196.
    Marinova Z, Walitza S, Grünblatt E (2013) 5-HT2A serotonin receptor agonist DOI alleviates cytotoxicity in neuroblastoma cells: role of the ERK pathway. Prog Neuro-Psychopharmacology Biol Psychiatry 44:64–72CrossRefGoogle Scholar
  197. 197.
    Seitz PK, Bremer NM, McGinnis AG et al (2012) Quantitative changes in intracellular calcium and extracellular-regulated kinase activation measured in parallel in CHO cells stably expressing serotonin (5-HT) 5-HT2A or 5-HT2C receptors. BMC Neurosci 13:25PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Cavanaugh JE, Ham J, Hetman M et al (2001) Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J Neurosci 21:434–443PubMedGoogle Scholar
  199. 199.
    Ying S-W, Futter M, Rosenblum K et al (2002) Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of arc synthesis. J Neurosci 22:1532–1540PubMedGoogle Scholar
  200. 200.
    Jones KA, Srivastava DP, Allen JA et al (2009) Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling. Proc Natl Acad Sci U S A 106:19575–19580PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Ohira K, Homma KJ, Hirai H et al (2006) TrkB-T1 regulates the RhoA signaling and actin cytoskeleton in glioma cells. Biochem Biophys Res Commun 342:867–874PubMedCrossRefGoogle Scholar
  202. 202.
    Yoshimura R, Ikenouchi-Sugita A, Hori H et al (2010) Adding a low dose atypical antipsychotic drug to an antidepressant induced a rapid increase of plasma brain-derived neurotrophic factor levels in patients with treatment-resistant depression. Prog Neuro-Psychopharmacology Biol Psychiatry 34:308–312CrossRefGoogle Scholar
  203. 203.
    Pillai A, Terry AV, Mahadik SP (2006) Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus. Schizophr Res 82:95–106PubMedCrossRefGoogle Scholar
  204. 204.
    L. Huang T (2013) Effects of antipsychotics on the BDNF in schizophrenia. Curr Med Chem 20:345–350Google Scholar
  205. 205.
    Benekareddy M, Nair AR, Dias BG et al (2013) Induction of the plasticity-associated immediate early gene arc by stress and hallucinogens: role of brain-derived neurotrophic factor. Int J Neuropsychopharmacol 16:405–415PubMedCrossRefGoogle Scholar
  206. 206.
    Vollenweider FX, Kometer M (2010) The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 11:642–651PubMedCrossRefGoogle Scholar
  207. 207.
    Bland ST, Tamlyn JP, Barrientos RM et al (2007) Expression of fibroblast growth factor-2 and brain-derived neurotrophic factor mRNA in the medial prefrontal cortex and hippocampus after uncontrollable or controllable stress. Neuroscience 144:1219–1228PubMedCrossRefGoogle Scholar
  208. 208.
    Lee Y, Duman RS, Marek GJ (2006) The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression. Neurosci Lett 398:328–332PubMedCrossRefGoogle Scholar
  209. 209.
    Gewirtz J (2000) Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23:569–576PubMedCrossRefGoogle Scholar
  210. 210.
    Kłodzinska A, Bijak M, Tokarski K, Pilc A (2002) Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice. Pharmacol Biochem Behav 73:327–332PubMedCrossRefGoogle Scholar
  211. 211.
    Zhang C, Marek GJ (2007) Group III metabotropic glutamate receptor agonists selectively suppress excitatory synaptic currents in the rat prefrontal cortex induced by 5-Hydroxytryptamine2A receptor activation. J Pharmacol Exp Ther 320:437–447PubMedCrossRefGoogle Scholar
  212. 212.
    Menezes MM, Santini MA, Benvenga MJ et al (2013) The mGlu2/3 receptor agonists LY354740 and LY379268 differentially regulate restraint-stress-induced expression of c-Fos in rat cerebral cortex. Neurosci J 2013:1–8CrossRefGoogle Scholar
  213. 213.
    Zhai Y, George CA, Zhai J et al (2003) Group II metabotropic glutamate receptor modulation of DOI-induced c-fos mRNA and excitatory responses in the cerebral cortex. Neuropsychopharmacology 28:45–52PubMedCrossRefGoogle Scholar
  214. 214.
    Benekareddy M, Goodfellow NM, Lambe EK, V a V (2010) Enhanced function of prefrontal serotonin 5-HT(2) receptors in a rat model of psychiatric vulnerability. J Neurosci 30:12138–12150PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Hemmerle AM, Ahlbrand R, Bronson SL et al (2015) Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation. Schizophr Res 168:411–420PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Malkova NV, Gallagher JJ, Yu CZ et al (2014) Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia. Proc Natl Acad Sci U S A 111:E2,492–E2,500CrossRefGoogle Scholar
  217. 217.
    Moreno JL, Kurita M, Holloway T et al (2011) Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT2A and mGlu2 receptors in the adult offspring. J Neurosci 31:1863–1872PubMedPubMedCentralCrossRefGoogle Scholar
  218. 218.
    Suri D, Bhattacharya A, Vaidya VA (2014) Early stress evokes temporally distinct consequences on the hippocampal transcriptome, anxiety and cognitive behaviour. Int J Neuropsychopharmacol 17:289–301PubMedCrossRefGoogle Scholar
  219. 219.
    Wang Q, Shao F, Wang W (2015) Maternal separation produces alterations of forebrain brain-derived neurotrophic factor expression in differently aged rats. Front Mol Neurosci 8:49PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Rogóz Z, Skuza G, Legutko B (2005) Repeated treatment with mirtazepine induces brain-derived neurotrophic factor gene expression in rats. J Physiol Pharmacol 56:661–671PubMedGoogle Scholar
  221. 221.
    Marek GJ, Martin-Ruiz R, Abo A, Artigas F (2005) The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30:2205–2215PubMedCrossRefGoogle Scholar
  222. 222.
    Liu R, Jolas T, Aghajanian G (2000) Serotonin 5-HT2 receptors activate local GABA inhibitory inputs to serotonergic neurons of the dorsal raphe nucleus. Brain Res 873:34–45PubMedCrossRefGoogle Scholar
  223. 223.
    Abdolmaleky HM, Yaqubi S, Papageorgis P et al (2011) Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. Schizophr Res 129:183–190PubMedCrossRefGoogle Scholar
  224. 224.
    Favalli G, Li J, Belmonte-de-Abreu P et al (2012) The role of BDNF in the pathophysiology and treatment of schizophrenia. J Psychiatr Res 46:1–11PubMedCrossRefGoogle Scholar
  225. 225.
    Golimbet VE, Lavrushina OM, Kaleda VG et al (2007) Supportive evidence for the association between the T102C 5-HTR2A gene polymorphism and schizophrenia: a large-scale case-control and family-based study. Eur Psychiatry 22:167–170PubMedCrossRefGoogle Scholar
  226. 226.
    Horacek J, Bubenikova-Valesova V, Kopecek M et al (2006) Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 20:389–409PubMedCrossRefGoogle Scholar
  227. 227.
    Lin P-Y (2012) Increase in brain-derived Neurotrophic factor in patients with schizophrenia treated with olanzapine: a systemic review and meta-analysis. J Exp Clin Med 4:119–124CrossRefGoogle Scholar
  228. 228.
    Angelucci F (2000) Mathé A a., Aloe L. Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration J Neurosci Res 60:783–794PubMedGoogle Scholar
  229. 229.
    Park DI, Kim HG, Jung WR et al (2011a) Mecamylamine attenuates dexamethasone-induced anxiety-like behavior in association with brain derived neurotrophic factor upregulation in rat brains. Neuropharmacology 61:276–282PubMedCrossRefGoogle Scholar
  230. 230.
    González-Maeso J, Yuen T, Ebersole BJ et al (2003) Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci 23:8836–8843PubMedGoogle Scholar
  231. 231.
    Djalali S, Höltje M, Grosse G et al (2005) Effects of brain-derived neurotrophic factor (BDNF) on glial cells and serotonergic neurones during development. J Neurochem 92:616–627PubMedCrossRefGoogle Scholar
  232. 232.
    Galter D, Unsicker K (1999) Regulation of the transmitter phenotype of rostral and caudal groups of cultured serotonergic raphe neurons. Neuroscience 88:549–559PubMedCrossRefGoogle Scholar
  233. 233.
    Galter D, Unsicker K (2000a) Brain-derived neurotrophic factor and trkB are essential for cAMP-mediated induction of the serotonergic neuronal phenotype. J Neurosci Res 61:295–301PubMedCrossRefGoogle Scholar
  234. 234.
    Mamounas LA, Altar CA, Blue ME et al (2000) BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci 20:771–782PubMedGoogle Scholar
  235. 235.
    Mamounas LA, Blue ME, Siuciak JA, Altar CA (1995) Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. J Neurosci 15:7929–7939PubMedGoogle Scholar
  236. 236.
    Galter D, Unsicker K (2000b) Sequential activation of the 5-HT1(a) serotonin receptor and TrkB induces the serotonergic neuronal phenotype. Mol Cell Neurosci 15:446–455PubMedCrossRefGoogle Scholar
  237. 237.
    Siuciak JA, Clark MS, Rind HB et al (1998) BDNF induction of tryptophan hydroxylase mRNA levels in the rat brain. J Neurosci Res 52:149–158PubMedCrossRefGoogle Scholar
  238. 238.
    Celada P, Siuciak JA, Tran TM et al (1996) Local infusion of brain-derived neurotrophic factor modifies the firing pattern of dorsal raphé serotonergic neurons. Brain Res 712:293–298PubMedCrossRefGoogle Scholar
  239. 239.
    Deltheil T, Guiard BP, Cerdan J et al (2008) Behavioral and serotonergic consequences of decreasing or increasing hippocampus brain-derived neurotrophic factor protein levels in mice. Neuropharmacology 55:1006–1014PubMedCrossRefGoogle Scholar
  240. 240.
    Naumenko VS, Kondaurova EM, Bazovkina DV et al (2012) Effect of brain-derived neurotrophic factor on behavior and key members of the brain serotonin system in genetically predisposed to behavioral disorders mouse strains. Neuroscience 214:59–67PubMedCrossRefGoogle Scholar
  241. 241.
    Tsybko AS, Il’chibaeva TV, Kondaurova EM et al (2014) Effect of central administration of the neurotrophic factors BDNF and GDNF on the functional activity and expression of 5-HT2A serotonin receptors in mice genetically predisposed to depressive-like behavior. Mol Biol 48:864–869CrossRefGoogle Scholar
  242. 242.
    Lyons WE, L a M, G a R et al (1999) Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A 96:15239–15244PubMedPubMedCentralCrossRefGoogle Scholar
  243. 243.
    Hensler JG, Ladenheim EE, Lyons WE (2003) Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/−) mice. J Neurochem 85:1139–1147PubMedCrossRefGoogle Scholar
  244. 244.
    Luellen BA, Bianco LE, Schneider LM, Andrews AM (2007) Reduced brain-derived neurotrophic factor is associated with a loss of serotonergic innervation in the hippocampus of aging mice. Genes Brain Behav 6:482–490PubMedCrossRefGoogle Scholar
  245. 245.
    Rios M, Lambe EK, Liu R et al (2006) Severe deficits in 5-HT2A -mediated neurotransmission in BDNF conditional mutant mice. J Neurobiol 66:408–420PubMedCrossRefGoogle Scholar
  246. 246.
    Chan JP, Unger TJ, Byrnes J, Rios M (2006) Examination of behavioral deficits triggered by targeting Bdnf in fetal or postnatal brains of mice. Neuroscience 142:49–58PubMedCrossRefGoogle Scholar
  247. 247.
    Sakata K, Duke SM (2014) Lack of BDNF expression through promoter IV disturbs expression of monoamine genes in the frontal cortex and hippocampus. Neuroscience 260:265–275PubMedCrossRefGoogle Scholar
  248. 248.
    Maynard KR, Hill JL, Calcaterra NE et al (2015) Functional role of BDNF production from unique promoters in aggression and serotonin Signaling. Neuropsychopharmacology.  https://doi.org/10.1038/npp.2015.349
  249. 249.
    Rios M, Fan G, Fekete C, Kelly J, Bates B, Kuehn R, Lechan RM, Jaenisch R (2001) Conditional Deletion Of Brain-Derived Neurotrophic Factor in the Postnatal Brain Leads to Obesity and Hyperactivity. Mol Endocrinol 15:1748–1757PubMedCrossRefGoogle Scholar
  250. 250.
    Sakata K, Woo NH, Martinowich K et al (2009) Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex. Proc Natl Acad Sci U S A 106:5942–5947PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Kim JH, Roberts DS, Hu Y, Lau GC, Brooks-Kayal AR, Farb DH, Russek SJ (2012) Brain-derived neurotrophic factor uses CREB and Egr3 to regulate NMDA receptor levels in cortical neurons. J Neurochem 120:210–219PubMedCrossRefGoogle Scholar
  252. 252.
    Roberts DS, Hu Y, Lund IV, Brooks-Kayal AR, Russek SJ (2006) Brain-derived Neurotrophic Factor (BDNF)-induced Synthesis of Early Growth Response Factor 3 (Egr3) Controls the Levels of Type A GABA Receptorα4 Subunits in Hippocampal Neurons. J Biol Chem 281:29431–29435PubMedCrossRefGoogle Scholar
  253. 253.
    Williams AA, Ingram WM, Levine S et al (2012) Reduced levels of serotonin 2A receptors underlie resistance of Egr3-deficient mice to locomotor suppression by clozapine. Neuropsychopharmacology 37:2285–2298PubMedPubMedCentralCrossRefGoogle Scholar
  254. 254.
    Maple AM, Zhao X, Elizalde DI et al (2015) Htr2a expression responds rapidly to environmental stimuli in an Egr3-dependent manner. ACS Chem Neurosci 6:1137–1142PubMedPubMedCentralCrossRefGoogle Scholar
  255. 255.
    Egan MF, Kojima M, Callicott JH et al (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269PubMedCrossRefGoogle Scholar
  256. 256.
    Henningsson S, Borg J, Lundberg J et al (2009) Genetic variation in brain-derived neurotrophic factor is associated with serotonin transporter but not serotonin-1A receptor availability in men. Biol Psychiatry 66:477–485PubMedCrossRefGoogle Scholar
  257. 257.
    Klein AB, Trajkovska V, Erritzoe D et al (2010a) Cerebral 5-HT2A receptor and serotonin transporter binding in humans are not affected by the val66met BDNF polymorphism status or blood BDNF levels. J Cereb Blood Flow Metab 30:e1–e7PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Willins DL, Meltzer HY (1997) Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J Pharmacol Exp Ther 282:699–706PubMedGoogle Scholar
  259. 259.
    Kuribara M, Eijsink VD, Roubos EW et al (2010) BDNF stimulates Ca2+ oscillation frequency in melanotrope cells of Xenopus Laevis: contribution of IP3-receptor-mediated release of intracellular Ca2+ to gene expression. Gen Comp Endocrinol 169:123–129PubMedCrossRefGoogle Scholar
  260. 260.
    Li YX, Zhang Y, Lester HA et al (1998) Enhancement of neurotransmitter release induced by brain-derived neurotrophic factor in cultured hippocampal neurons. J Neurosci 18:10231–10240PubMedGoogle Scholar
  261. 261.
    Jørgensen H, Knigge U, Kjaer A et al (1998) Serotonergic involvement in stress-induced ACTH release. Brain Res 811:10–20PubMedCrossRefGoogle Scholar
  262. 262.
    Bath KG, Schilit A, Lee FS (2013) Stress effects on BDNF expression: effects of age, sex, and form of stress. Neuroscience 239:149–156PubMedCrossRefGoogle Scholar
  263. 263.
    Castrén E, Võikar V, Rantamäki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7:18–21PubMedCrossRefGoogle Scholar
  264. 264.
    Holloway T, Moreno JL, Umali A et al (2013) Prenatal stress induces schizophrenia-like alterations of serotonin 2A and metabotropic glutamate 2 receptors in the adult offspring: role of maternal immune system. J Neurosci 33:1088–1098PubMedPubMedCentralCrossRefGoogle Scholar
  265. 265.
    Matuszewich L, Yamamoto BK (2003) Long-lasting effects of chronic stress on DOI-induced hyperthermia in male rats. Psychopharmacology 169:169–175PubMedCrossRefGoogle Scholar
  266. 266.
    Harvey ML, Swallows CL, Cooper MA (2012) A double dissociation in the effects of 5-HT2A and 5-HT2C receptors on the acquisition and expression of conditioned defeat in Syrian hamsters. Behav Neurosci 126:530–537PubMedPubMedCentralCrossRefGoogle Scholar
  267. 267.
    Benekareddy M, Vadodaria KC, Nair AR, Vaidya VA (2011) Postnatal serotonin type 2 receptor blockade prevents the emergence of anxiety behavior, dysregulated stress-induced immediate early gene responses, and specific transcriptional changes that arise following early life stress. Biol Psychiatry 70:1024–1032PubMedPubMedCentralCrossRefGoogle Scholar
  268. 268.
    Adamec R, Creamer K, Bartoszyk GD, Burton P (2004) Prophylactic and therapeutic effects of acute systemic injections of EMD 281014, a selective serotonin 2A receptor antagonist on anxiety induced by predator stress in rats. Eur J Pharmacol 504:79–96PubMedCrossRefGoogle Scholar
  269. 269.
    Beig MI, Baumert M, Walker FR et al (2009) Blockade of 5-HT2A receptors suppresses hyperthermic but not cardiovascular responses to psychosocial stress in rats. Neuroscience 159:1185–1191PubMedCrossRefGoogle Scholar
  270. 270.
    Ootsuka Y, Blessing WW, Nalivaiko E (2008) Selective blockade of 5-HT2A receptors attenuates the increased temperature response in brown adipose tissue to restraint stress in rats. Stress 11:125–133PubMedCrossRefGoogle Scholar
  271. 271.
    Pehek EA, Nocjar C, Roth BL et al (2006) Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology 31:265–277PubMedCrossRefGoogle Scholar
  272. 272.
    Grønli J, Bramham C, Murison R et al (2006) Chronic mild stress inhibits BDNF protein expression and CREB activation in the dentate gyrus but not in the hippocampus proper. Pharmacol Biochem Behav 85:842–849PubMedCrossRefGoogle Scholar
  273. 273.
    Krishnan V, Nestler EJ (2008) The molecular neurobiology of depression. Nature 455:894–902PubMedPubMedCentralCrossRefGoogle Scholar
  274. 274.
    Lee B-H, Kim Y-K (2010) The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig 7:231–235PubMedPubMedCentralCrossRefGoogle Scholar
  275. 275.
    Nowacka M, Obuchowicz E (2013) BDNF and VEGF in the pathogenesis of stress-induced affective diseases: an insight from experimental studies. Pharmacol Rep 65:535–546PubMedCrossRefGoogle Scholar
  276. 276.
    Marmigère F, Givalois L, Rage F et al (2003) Rapid induction of BDNF expression in the hippocampus during immobilization stress challenge in adult rats. Hippocampus 13:646–655PubMedCrossRefGoogle Scholar
  277. 277.
    Molteni R, Calabrese F, Cattaneo A et al (2009) Acute stress responsiveness of the neurotrophin BDNF in the rat hippocampus is modulated by chronic treatment with the antidepressant duloxetine. Neuropsychopharmacology 34:1523–1532PubMedCrossRefGoogle Scholar
  278. 278.
    Dranovsky A, Hen R (2006) Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 59:1136–1143PubMedCrossRefGoogle Scholar
  279. 279.
    Lu B, Chang JH (2004) Regulation of neurogenesis by neurotrophins: implications in hippocampus-dependent memory. Neuron Glia Biol 1:377–384PubMedCrossRefGoogle Scholar
  280. 280.
    McEwen BS (2000) Effects of adverse experiences for brain structure and function. Biol Psychiatry 48:721–731PubMedCrossRefGoogle Scholar
  281. 281.
    Pittenger C, Duman RS (2008) Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33:88–109PubMedCrossRefGoogle Scholar
  282. 282.
    Kim JJ, Diamond DM (2002) The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 3:453–462PubMedCrossRefGoogle Scholar
  283. 283.
    Pavlides C, Nivón LG, McEwen BS (2002) Effects of chronic stress on hippocampal long-term potentiation. Hippocampus 12:245–257PubMedCrossRefGoogle Scholar
  284. 284.
    Bennett MR, Lagopoulos J (2014) Stress and trauma: BDNF control of dendritic-spine formation and regression. Prog Neurobiol 112:80–99PubMedCrossRefGoogle Scholar
  285. 285.
    Govindarajan A, Rao BSS, Nair D et al (2006) Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proc Natl Acad Sci U S A 103:13208–13213PubMedPubMedCentralCrossRefGoogle Scholar
  286. 286.
    Liu R-J, Aghajanian GK (2008) Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc Natl Acad Sci U S A 105:359–364PubMedPubMedCentralCrossRefGoogle Scholar
  287. 287.
    Watanabe Y, Gould E, Daniels DC et al (1992) Tianeptine attenuates stress-induced morphological changes in the hippocampus. Eur J Pharmacol 222:157–162PubMedCrossRefGoogle Scholar
  288. 288.
    Czéh B, Michaelis T, Watanabe T et al (2001) Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A 98:12796–12801PubMedPubMedCentralCrossRefGoogle Scholar
  289. 289.
    Jiang X, Xing G, Yang C et al (2009) Stress impairs 5-HT2A receptor-mediated serotonergic facilitation of GABA release in juvenile rat basolateral amygdala. Neuropsychopharmacology 34:410–423PubMedCrossRefGoogle Scholar
  290. 290.
    Popoli M, Yan Z, McEwen BS, Sanacora G (2012) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13:22–37CrossRefGoogle Scholar
  291. 291.
    Treccani G, Musazzi L, Perego C et al (2014) Stress and corticosterone increase the readily releasable pool of glutamate vesicles in synaptic terminals of prefrontal and frontal cortex. Mol Psychiatry 19:433–443PubMedCrossRefGoogle Scholar
  292. 292.
    Bland ST, Schmid MJ, Der-Avakian A et al (2005) Expression of c-fos and BDNF mRNA in subregions of the prefrontal cortex of male and female rats after acute uncontrollable stress. Brain Res 1051:90–99PubMedCrossRefGoogle Scholar
  293. 293.
    Pandey DK, Bhatt S, Jindal A, Gautam B (2014) Effect of combination of ketanserin and escitalopram on behavioral anomalies after olfactory bulbectomy: prediction of quick onset of antidepressant action. Indian J Pharmacol 46:639–643PubMedPubMedCentralCrossRefGoogle Scholar
  294. 294.
    Quesseveur G, Repérant C, David DJ et al (2013) 5-HT2A receptor inactivation potentiates the acute antidepressant-like activity of escitalopram: involvement of the noradrenergic system. Exp Brain Res 226:285–295PubMedCrossRefGoogle Scholar
  295. 295.
    Sibille E, Sarnyai Z, Benjamin D et al (1997) Antisense inhibition of 5-hydroxytryptamine2a receptor induces an antidepressant-like effect in mice. Mol Pharmacol 52:1056–1063PubMedCrossRefGoogle Scholar
  296. 296.
    Choi M-J, Lee H-J, Lee H-J et al (2004) Association between major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor gene. Neuropsychobiology 49:38–41PubMedCrossRefGoogle Scholar
  297. 297.
    Jin C, Xu W, Yuan J et al (2013) Meta-analysis of association between the -1438A/G (rs6311) polymorphism of the serotonin 2A receptor gene and major depressive disorder. Neurol Res 35:7–14PubMedCrossRefGoogle Scholar
  298. 298.
    Horstmann S, Lucae S, Menke A et al (2010) Polymorphisms in GRIK4, HTR2A, and FKBP5 show interactive effects in predicting remission to antidepressant treatment. Neuropsychopharmacology 35:727–740PubMedCrossRefGoogle Scholar
  299. 299.
    Lucae S, Ising M, Horstmann S et al (2010) HTR2A gene variation is involved in antidepressant treatment response. Eur Neuropsychopharmacol 20:65–68PubMedCrossRefGoogle Scholar
  300. 300.
    McMahon FJ, Buervenich S, Charney D et al (2006) Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet 78:804–814PubMedPubMedCentralCrossRefGoogle Scholar
  301. 301.
    Viikki M, Huuhka K, Leinonen E et al (2011) Interaction between two HTR2A polymorphisms and gender is associated with treatment response in MDD. Neurosci Lett 501:20–24PubMedCrossRefGoogle Scholar
  302. 302.
    Blier P (2003) The pharmacology of putative early-onset antidepressant strategies. Eur Neuropsychopharmacol 13:57–66PubMedCrossRefGoogle Scholar
  303. 303.
    Lopes Rocha F, Fuzikawa C, Riera R et al (2013) Antidepressant combination for major depression in incomplete responders--a systematic review. J Affect Disord 144:1–6Google Scholar
  304. 304.
    Rocha FL, Fuzikawa C, Riera R, Hara C (2012) Combination of antidepressants in the treatment of major depressive disorder: a systematic review and meta-analysis. J Clin Psychopharmacol 32:278–281PubMedCrossRefGoogle Scholar
  305. 305.
    Frokjaer VG, Mortensen EL, Nielsen FA et al (2008) Frontolimbic serotonin 2A receptor binding in healthy subjects is associated with personality risk factors for affective disorder. Biol Psychiatry 63:569–576PubMedCrossRefGoogle Scholar
  306. 306.
    McKeith IG, Marshall EF, Ferrier IN et al (1987) 5-HT receptor binding in post-mortem brain from patients with affective disorder. J Affect Disord 13:67–74PubMedCrossRefGoogle Scholar
  307. 307.
    Oquendo MA, Russo SA, Underwood MD et al (2006) Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide. Biol Psychiatry 59:235–243PubMedCrossRefGoogle Scholar
  308. 308.
    Serres F, Azorin JM, Valli M, Jeanningros R (1999) Evidence for an increase in functional platelet 5-HT2A receptors in depressed patients using the new ligand [125I]-DOI. Eur Psychiatry 14:451–457PubMedCrossRefGoogle Scholar
  309. 309.
    Li Y, Luikart BW, Birnbaum S et al (2008) TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 59:399–412PubMedPubMedCentralCrossRefGoogle Scholar
  310. 310.
    Castrén E, Rantamäki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol 70:289–297PubMedCrossRefGoogle Scholar
  311. 311.
    Kavalali ET, Monteggia LM (2012) Synaptic mechanisms underlying rapid antidepressant action of ketamine. Am J Psychiatry 169:1150–1156PubMedCrossRefGoogle Scholar
  312. 312.
    Adachi M, Barrot M, Autry AE et al (2008) Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry 63:642–649PubMedCrossRefGoogle Scholar
  313. 313.
    Eisch AJ, Bolaños CA, de Wit J et al (2003) Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol Psychiatry 54:994–1005PubMedCrossRefGoogle Scholar
  314. 314.
    Koponen E, Rantamäki T, Voikar V et al (2005) Enhanced BDNF signaling is associated with an antidepressant-like behavioral response and changes in brain monoamines. Cell Mol Neurobiol 25:973–980PubMedCrossRefGoogle Scholar
  315. 315.
    Lepack AE, Fuchikami M, Dwyer JM et al (2014) BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 18(1):pyu033PubMedPubMedCentralCrossRefGoogle Scholar
  316. 316.
    Monteggia LM, Barrot M, Powell CM et al (2004) Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci U S A 101:10827–10832PubMedPubMedCentralCrossRefGoogle Scholar
  317. 317.
    Saarelainen T, Hendolin P, Lucas G et al (2003) Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23:349–357PubMedGoogle Scholar
  318. 318.
    Shirayama Y, Chen AC-H, Nakagawa S et al (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22:3251–3261PubMedGoogle Scholar
  319. 319.
    Taliaz D, Nagaraj V, Haramati S et al (2013) Altered brain-derived neurotrophic factor expression in the ventral tegmental area, but not in the hippocampus, is essential for antidepressant-like effects of electroconvulsive therapy. Biol Psychiatry 74:305–312PubMedCrossRefGoogle Scholar
  320. 320.
    Björkholm C, Monteggia LM (2016) BDNF- a key transducer of antidepressant effects. Neuropharmacology 102:72–79PubMedCrossRefGoogle Scholar
  321. 321.
    Duman RS, Li N (2012) A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond Ser B Biol Sci 367:2475–2484CrossRefGoogle Scholar
  322. 322.
    Schmidt HD, Duman RS (2007) The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior. Behav Pharmacol 18:391–418PubMedCrossRefGoogle Scholar
  323. 323.
    Wang J-W, Dranovsky A, Hen R (2008) The when and where of BDNF and the antidepressant response. Biol Psychiatry 63:640–641PubMedCrossRefGoogle Scholar
  324. 324.
    Chiaruttini C, Vicario A, Li Z et al (2009) Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation. Proc Natl Acad Sci U S A 106:16481–16486PubMedPubMedCentralCrossRefGoogle Scholar
  325. 325.
    Colle R, Deflesselle E, Martin S et al (2015) BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients. Pharmacogenomics 16:997–1013PubMedCrossRefGoogle Scholar
  326. 326.
    Hosang GM, Shiles C, Tansey KE et al (2014) Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis. BMC Med 12:7PubMedPubMedCentralCrossRefGoogle Scholar
  327. 327.
    Schumacher J, Jamra RA, Becker T et al (2005) Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry 58:307–314PubMedCrossRefGoogle Scholar
  328. 328.
    Bath KG, Jing DQ, Dincheva I et al (2012) BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity. Neuropsychopharmacology 37:1297–1304PubMedPubMedCentralCrossRefGoogle Scholar
  329. 329.
    Chen Z-Y, Jing D, Bath KG et al (2006) Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314:140–143PubMedPubMedCentralCrossRefGoogle Scholar
  330. 330.
    Liu R-J, Lee FS, Li X-Y et al (2012) Brain-derived Neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 71:996–1005PubMedCrossRefGoogle Scholar
  331. 331.
    Yu H, Wang D-D, Wang Y et al (2012) Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J Neurosci 32:4092–4101PubMedPubMedCentralCrossRefGoogle Scholar
  332. 332.
    Masi G, Brovedani P (2011) The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression. CNS Drugs 25:913–931PubMedCrossRefGoogle Scholar
  333. 333.
    Marek GJ (2008) Regulation of rat cortical 5-hydroxytryptamine2A receptor-mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine. Eur Neuropsychopharmacol 18:498–507PubMedPubMedCentralCrossRefGoogle Scholar
  334. 334.
    Muguruza C, Miranda-Azpiazu P, Díez-Alarcia R et al (2014) Evaluation of 5-HT2A and mGlu2/3 receptors in postmortem prefrontal cortex of subjects with major depressive disorder: effect of antidepressant treatment. Neuropharmacology 86:311–318PubMedCrossRefGoogle Scholar
  335. 335.
    Kusumi I, Boku S, Takahashi Y (2015) Psychopharmacology of atypical antipsychotic drugs: from the receptor binding profile to neuroprotection and neurogenesis. Psychiatry Clin Neurosci 69:243–258PubMedCrossRefGoogle Scholar
  336. 336.
    Nandra KS, Agius M (2012) The differences between typical and atypical antipsychotics: the effects on neurogenesis. Psychiatr Danub 24(Suppl 1):S95–S99PubMedGoogle Scholar
  337. 337.
    Park SW, Phuong VT, Lee CH et al (2011b) Effects of antipsychotic drugs on BDNF, GSK-3β, and β-catenin expression in rats subjected to immobilization stress. Neurosci Res 71:335–340PubMedCrossRefGoogle Scholar
  338. 338.
    Buckley PF, Pillai A, Howell KR (2011) Brain-derived neurotrophic factor: findings in schizophrenia. Curr Opin Psychiatry 24:122–127PubMedCrossRefGoogle Scholar
  339. 339.
    Pandya CD, Kutiyanawalla A, Pillai A (2013) BDNF-TrkB signaling and neuroprotection in schizophrenia. Asian J Psychiatr 6:22–28PubMedCrossRefGoogle Scholar
  340. 340.
    Ray MT, Shannon Weickert C, Webster MJ (2014) Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders. Transl Psychiatry 4:e389PubMedPubMedCentralCrossRefGoogle Scholar
  341. 341.
    Hashimoto T, Bergen SE, Nguyen QL et al (2005) Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 25:372–383PubMedCrossRefGoogle Scholar
  342. 342.
    Pillai A (2008) Brain-derived neurotropic factor/TrkB signaling in the pathogenesis and novel pharmacotherapy of schizophrenia. Neurosignals 16:183–193PubMedCrossRefGoogle Scholar
  343. 343.
    Gonzalez-Burgos G, Cho RY, Lewis DA (2015) Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry 77:1031–1040PubMedPubMedCentralCrossRefGoogle Scholar
  344. 344.
    Inan M, Petros TJ, Anderson SA (2013) Losing your inhibition: linking cortical GABAergic interneurons to schizophrenia. Neurobiol Dis 53:36–48PubMedCrossRefGoogle Scholar
  345. 345.
    Nakazawa K, Zsiros V, Jiang Z et al (2012) GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology 62:1574–1583PubMedCrossRefGoogle Scholar
  346. 346.
    Brown JA, Ramikie TS, Schmidt MJ et al (2015) Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Mol Psychiatry 20(12):1499–1507PubMedPubMedCentralCrossRefGoogle Scholar
  347. 347.
    Nakamura T, Matsumoto J, Takamura Y et al (2015) Relationships among parvalbumin-immunoreactive neuron density, phase-locked gamma oscillations, and autistic/schizophrenic symptoms in PDGFR-β knock-out and control mice. PLoS One 10:e0119258PubMedPubMedCentralCrossRefGoogle Scholar
  348. 348.
    Shen S, Lang B, Nakamoto C et al (2008) Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1. J Neurosci 28:10893–10904PubMedCrossRefGoogle Scholar
  349. 349.
    Mellios N, Huang H-S, Baker SP et al (2009) Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry 65:1006–1014PubMedCrossRefGoogle Scholar
  350. 350.
    Weber ET, Andrade R (2010) Htr2a gene and 5-HT(2A) receptor expression in the cerebral cortex studied using genetically modified mice. Front Neurosci 4:36PubMedPubMedCentralGoogle Scholar
  351. 351.
    Seo MK, Lee CH, Cho HY et al (2015) Effects of antipsychotic drugs on the expression of synapse-associated proteins in the frontal cortex of rats subjected to immobilization stress. Psychiatry Res 229:968–974PubMedCrossRefGoogle Scholar
  352. 352.
    Angelucci F, Aloe L, Iannitelli A et al (2005) Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain. Eur Neuropsychopharmacol 15:311–317PubMedCrossRefGoogle Scholar
  353. 353.
    Park SW, Lee CH, Cho HY et al (2013) Effects of antipsychotic drugs on the expression of synaptic proteins and dendritic outgrowth in hippocampal neuronal cultures. Synapse 67:224–234PubMedCrossRefGoogle Scholar
  354. 354.
    Newton SS, Duman RS (2007) Neurogenic actions of atypical antipsychotic drugs and therapeutic implications. CNS Drugs 21(9):715–725PubMedCrossRefGoogle Scholar
  355. 355.
    Halberstadt AL, Nichols DE (2010) Handbook of the Behavioral neurobiology of serotonin. Elsevier 4(7):621Google Scholar
  356. 356.
    Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181PubMedCrossRefGoogle Scholar
  357. 357.
    Halpern JH, Pope HG (2003) Hallucinogen persisting perception disorder: what do we know after 50 years? Drug Alcohol Depend 69:109–119PubMedCrossRefGoogle Scholar
  358. 358.
    Guirado R, Perez-Rando M, Sanchez-Matarredona D et al (2014) Chronic fluoxetine treatment alters the structure, connectivity and plasticity of cortical interneurons. Int J Neuropsychopharmacol 17:1635–1646PubMedCrossRefGoogle Scholar
  359. 359.
    Kepser LJ, Homberg JR (2015) The neurodevelopmental effects of serotonin: a behavioural perspective. Behav Brain Res 277:3–13PubMedCrossRefGoogle Scholar
  360. 360.
    Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, O’Leary OF, Castrén E, Maffei L (2008) The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320(5874):385–388Google Scholar
  361. 361.
    Cabelli RJ, Hohn A, Shatz CJ (1995) Inhibition of ocular dominance column formation by infusion of NT-4/5 or BDNF. Science 267:1662–1666PubMedCrossRefGoogle Scholar
  362. 362.
    Hata Y, Ohshima M, Ichisaka S et al (2000) Brain-derived neurotrophic factor expands ocular dominance columns in visual cortex in monocularly deprived and nondeprived kittens but does not in adult cats. J Neurosci 20:RC57PubMedGoogle Scholar
  363. 363.
    Huang ZJ, Kirkwood A, Pizzorusso T et al (1999) BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98:739–755PubMedCrossRefGoogle Scholar
  364. 364.
    Roth TL, Lubin FD, Funk AJ, Sweatt JD (2009) Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 65:760–769PubMedPubMedCentralCrossRefGoogle Scholar
  365. 365.
    Cargnin S, Massarotti A, Terrazzino S (2016) BDNF Val66Met and clinical response to antipsychotic drugs: a systematic review and meta-analysis. Eur Psychiatry Mar:45–53Google Scholar
  366. 366.
    Notaras M, Hill R, van den Buuse M (2015b) The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy. Mol Psychiatry 20:916–930PubMedCrossRefGoogle Scholar
  367. 367.
    Serretti A, Drago A, De Ronchi D (2007) HTR2A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies. 14: 2053–2069Google Scholar
  368. 368.
    Shinozaki G, Romanowicz M, Marek DA, Kung S (2013) HTR2A gene-child abuse interaction and association with a history of suicide attempt among Caucasian depressed psychiatric inpatients. J Affect Disord 150:1200–1203PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Biological SciencesTata Institute of Fundamental ResearchMumbaiIndia

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