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Extracellular Signal-Regulated Kinase 2 Signaling in the Hippocampal Dentate Gyrus Mediates the Antidepressant Effects of Testosterone

  • Nicole Carrier
    Affiliations
    Department of Biomedical Sciences, Program in Neurosciences, College of Medicine, Florida State University
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  • Mohamed Kabbaj
    Correspondence
    Address correspondence to Mohamed Kabbaj, Ph.D., Associate Professor, Biomedical Sciences & Neurosciences, College of Medicine, 1115 West Call Street, Tallahassee, FL 32306
    Affiliations
    Department of Biomedical Sciences, Program in Neurosciences, College of Medicine, Florida State University
    Search for articles by this author

      Background

      Human and animal studies suggest that testosterone may have antidepressant effects. In this study, we sought to investigate the molecular mechanisms underlying the antidepressant effects of testosterone within the hippocampus, an area that is fundamental in the etiology of depression.

      Methods

      The effects of testosterone replacements in gonadectomized adult male rats were investigated using the sucrose preference and forced swim tests. We explored possible effects of testosterone on hippocampal neurogenesis and gene expression of stress-related molecules. Through the use of viral vectors, we pursued the antidepressant molecular mechanism(s) of testosterone in mediating anhedonia and manipulated extracellular signal-regulated kinase 2 (ERK2) expression in the dentate gyrus in gonadectomized rats with testosterone replacements.

      Results

      Testosterone had antidepressant effects, likely mediated by aromatization to estrogen metabolites, in the sucrose preference and forced swim tests despite having no effects on hippocampal cell proliferation or survival. We found a testosterone-dependent regulation of hippocampal ERK2 expression. Functionally, reducing ERK2 activity within the dentate gyrus induced anhedonia in gonadectomized rats receiving testosterone supplementation, whereas the overexpression of ERK2 rescued this behavior in gonadectomized rats.

      Conclusions

      These results implicate a role for ERK2 signaling within the dentate gyrus area of the hippocampus as a key mediator of the antidepressant effects of testosterone.

      Key Words

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      References

        • Earls F.
        Sex differences in psychiatric disorders: Origins and developmental influences.
        Psychiatr Dev. 1987; 5: 1-23
        • Angst J.
        • Gamma A.
        • Gastpar M.
        • Lepine J.P.
        • Mendlewicz J.
        • Tylee A.
        Gender differences in depression.
        Eur Arch Psychiatry Clin Neurosci. 2002; 252: 201-209
        • Bebbington P.
        • Dunn G.
        • Jenkins R.
        • Lewis G.
        • Brugha T.
        • Farrell M.
        • et al.
        The influence of age and sex on the prevalence of depressive conditions: Report from the National Survey of Psychiatric Morbidity.
        Int Rev Psychiatry. 2003; 15: 74-83
        • Kessler R.C.
        Epidemiology of women and depression.
        J Affect Disord. 2003; 74: 5-13
        • Kanayama G.
        • Amiaz R.
        • Seidman S.
        • Pope Jr, H.G.
        Testosterone supplementation for depressed men: current research and suggested treatment guidelines.
        Exp Clin Psychopharmacol. 2007; 15: 529-538
        • McIntyre R.S.
        • Mancini D.
        • Eisfeld B.S.
        • Soczynska J.K.
        • Grupp L.
        • Konarski J.Z.
        • et al.
        Calculated bioavailable testosterone levels and depression in middle-aged men.
        Psychoneuroendocrinology. 2006; 31: 1029-1035
        • Cunningham G.R.
        • Cordero E.
        • Thornby J.I.
        Testosterone replacement with transdermal therapeutic systems.
        JAMA. 1989; 261: 2525-2530
        • McNicholas T.A.
        • Dean J.D.
        • Mulder H.
        • Carnegie C.
        • Jones N.A.
        A novel testosterone gel formulation normalizes androgen levels in hypogonadal men, with improvements in body composition and sexual function.
        BJU Int. 2003; 91: 69-74
        • Vermeulen A.
        • Kaufman J.M.
        Diagnosis of hypogonadism in the aging male.
        Aging Male. 2002; 5: 170-176
        • Frye C.A.
        • Walf A.A.
        Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites.
        Physiol Behav. 2009; 97: 266-269
        • Solomon M.B.
        • Karom M.C.
        • Norvelle A.
        • Markham C.A.
        • Erwin W.D.
        • Huhman K.L.
        Gonadal hormones modulate the display of conditioned defeat in male Syrian hamsters.
        Horm Behav. 2009; 56: 423-428
        • Krishnan V.
        • Nestler E.J.
        The molecular neurobiology of depression.
        Nature. 2008; 455: 894-902
        • Malberg J.E.
        • Eisch A.J.
        • Nestler E.J.
        • Duman R.S.
        Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.
        J Neurosci. 2000; 20: 9104-9110
        • Perera T.D.
        • Coplan J.D.
        • Lisanby S.H.
        • Lipira C.M.
        • Arif M.
        • Carpio C.
        • et al.
        Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates.
        J Neurosci. 2007; 27: 4894-4901
        • Madsen T.M.
        • Treschow A.
        • Bengzon J.
        • Bolwig T.G.
        • Lindvall O.
        • Tingstrom A.
        Increased neurogenesis in a model of electroconvulsive therapy.
        Biol Psychiatry. 2000; 47: 1043-1049
        • van Praag H.
        • Christie B.R.
        • Sejnowski T.J.
        • Gage F.H.
        Running enhances neurogenesis, learning, and long-term potentiation in mice.
        Proc Natl Acad Sci U S A. 1999; 96: 13427-13431
        • 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
        • Warner-Schmidt J.L.
        • Duman R.S.
        Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment.
        Hippocampus. 2006; 16: 239-249
        • Holsboer F.
        Stress, hypercortisolism and corticosteroid receptors in depression: Implications for therapy.
        J Affect Disord. 2001; 62: 77-91
        • Lopez J.F.
        • Vazquez D.M.
        • Chalmers D.T.
        • Watson S.J.
        Regulation of 5-HT receptors and the hypothalamic-pituitary-adrenal axis.
        Ann N Y Acad Sci. 1997; 836: 106-134
        • Anacker C.
        • Zunszain P.A.
        • Carvalho L.A.
        • Pariante C.M.
        The glucocorticoid receptor: Pivot of depression and of antidepressant treatment?.
        Psychoneuroendocrinology. 2011; 36: 415-425
        • Migliaccio A.
        • Castoria G.
        • Di Domenico M.
        • de Falco A.
        • Bilancio A.
        • Lombardi M.
        • et al.
        Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation.
        EMBO J. 2000; 19: 5406-5417
        • 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
        • Einat H.
        • Yuan P.
        • Gould T.D.
        • Li J.
        • Du J.
        • Zhang L.
        • et al.
        The role of the extracellular signal-regulated kinase signaling pathway in mood modulation.
        J Neurosci. 2003; 23: 7311-7316
        • Qi X.
        • Lin W.
        • Li J.
        • Pan Y.
        • Wang W.
        The depressive-like behaviors are correlated with decreased phosphorylation of mitogen-activated protein kinases in rat brain following chronic forced swim stress.
        Behav Brain Res. 2006; 175: 233-240
        • Spritzer M.D.
        • Galea L.A.
        Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats.
        Dev Neurobiol. 2007; 67: 1321-1333
        • Robinson M.J.
        • Harkins P.C.
        • Zhang J.
        • Baer R.
        • Haycock J.W.
        • Cobb M.H.
        • et al.
        Mutation of position 52 in ERK2 creates a nonproductive binding mode for adenosine 5'-triphosphate.
        Biochemistry. 1996; 35: 5641-5646
        • Neve R.L.
        • Howe J.R.
        • Hong S.
        • Kalb R.G.
        Introduction of the glutamate receptor subunit 1 into motor neurons in vitro and in vivo using a recombinant herpes simplex virus.
        Neuroscience. 1997; 79: 435-447
        • 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
        • Russo S.J.
        • Bolanos C.A.
        • Theobald D.E.
        • DeCarolis N.A.
        • Renthal W.
        • Kumar A.
        • et al.
        IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates.
        Nature Neurosci. 2007; 10: 93-99
        • 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
        • Paxinos G.W.C.
        The Rat Brain in Stereotaxic Coordinates.
        3rd ed. Academic Press, San Diego, CA1998
        • Carlezon Jr, W.A.
        • Thome J.
        • Olson V.G.
        • Lane-Ladd S.B.
        • Brodkin E.S.
        • Hiroi N.
        • et al.
        Regulation of cocaine reward by CREB.
        Science. 1998; 282: 2272-2275
        • Barrot M.
        • Olivier J.D.
        • Perrotti L.I.
        • DiLeone R.J.
        • Berton O.
        • Eisch A.J.
        • et al.
        CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli.
        Proc Natl Acad Sci U S A. 2002; 99: 11435-11440
      1. Hollis F, Duclot F, Gunjan A, Kabbaj M Individual differences in the effect of social defeat on anhedonia and histone acetylation in the rat hippocampus. Horm Behav 59:331–337.

        • Lucki I.
        The forced swimming test as a model for core and component behavioral effects of antidepressant drugs.
        Behav Pharmacol. 1997; 8: 523-532
        • Gundersen H.J.
        • Bendtsen T.F.
        • Korbo L.
        • Marcussen N.
        • Moller A.
        • Nielsen K.
        • et al.
        Some new, simple and efficient stereological methods and their use in pathological research and diagnosis.
        APMIS. 1988; 96: 379-394
        • Adler A.
        • Vescovo P.
        • Robinson J.K.
        • Kritzer M.F.
        Gonadectomy in adult life increases tyrosine hydroxylase immunoreactivity in the prefrontal cortex and decreases open field activity in male rats.
        Neuroscience. 1999; 89: 939-954
        • Gentry R.T.
        • Wade G.N.
        Androgenic control of food intake and body weight in male rats.
        J Comp Physiol Psychol. 1976; 90: 18-25
        • Buwalda B.
        • van der Borght K.
        • Koolhaas J.M.
        • McEwen B.S.
        Testosterone decrease does not play a major role in the suppression of hippocampal cell proliferation following social defeat stress in rats.
        Physiol Behav. 2010; 101: 719-725
        • Vollmayr B.
        • Simonis C.
        • Weber S.
        • Gass P.
        • Henn F.
        Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness.
        Biol Psychiatry. 2003; 54: 1035-1040
        • Reif A.
        • Fritzen S.
        • Finger M.
        • Strobel A.
        • Lauer M.
        • Schmitt A.
        • et al.
        Neural stem cell proliferation is decreased in schizophrenia, but not in depression.
        Mol Psychiatry. 2006; 11: 514-522
        • Bessa J.M.
        • Ferreira D.
        • Melo I.
        • Marques F.
        • Cerqueira J.J.
        • Palha J.A.
        • et al.
        The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling.
        Mol Psychiatry. 2009; 14 (739): 764-773
        • Holick K.A.
        • Lee D.C.
        • Hen R.
        • Dulawa S.C.
        Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor.
        Neuropsychopharmacology. 2008; 33: 406-417
        • Huang G.J.
        • Bannerman D.
        • Flint J.
        Chronic fluoxetine treatment alters behavior, but not adult hippocampal neurogenesis, in BALB/cJ mice.
        Mol Psychiatry. 2008; 13: 119-121
        • Gillespie C.F.
        • Nemeroff C.B.
        Hypercortisolemia and depression.
        Psychosom Med. 2005; 67: S26-S28
        • Sapolsky R.M.
        Stress hormones: good and bad.
        Neurobiol Dis. 2000; 7: 540-542
        • Pariante C.M.
        • Miller A.H.
        Glucocorticoid receptors in major depression: Relevance to pathophysiology and treatment.
        Biol Psychiatry. 2001; 49: 391-404
        • Barden N.
        Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression.
        J Psychiatry Neurosci. 2004; 29: 185-193
        • McEwen B.S.
        Physiology and neurobiology of stress and adaptation: Central role of the brain.
        Physiol Rev. 2007; 87: 873-904
        • Duman R.S.
        Role of neurotrophic factors in the etiology and treatment of mood disorders.
        Neuromol Med. 2004; 5: 11-25
        • Duman R.S.
        • Heninger G.R.
        • Nestler E.J.
        A molecular and cellular theory of depression.
        Arch Gen Psychiatry. 1997; 54: 597-606
        • Nestler E.J.
        • Barrot M.
        • DiLeone R.J.
        • Eisch A.J.
        • Gold S.J.
        • Monteggia L.M.
        Neurobiology of depression.
        Neuron. 2002; 34: 13-25
        • 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
        • Chen Z.
        • Gibson T.B.
        • Robinson F.
        • Silvestro L.
        • Pearson G.
        • Xu B.
        • et al.
        MAP kinases.
        Chem Rev. 2001; 101: 2449-2476
        • Schafe G.E.
        • Atkins C.M.
        • Swank M.W.
        • Bauer E.P.
        • Sweatt J.D.
        • LeDoux J.E.
        Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning.
        J Neurosci. 2000; 20: 8177-8187
        • Sweatt J.D.
        The neuronal MAP kinase cascade: A biochemical signal integration system subserving synaptic plasticity and memory.
        J Neurochem. 2001; 76: 1-10
        • Cheng J.
        • Watkins S.C.
        • Walker W.H.
        Testosterone activates mitogen-activated protein kinase via Src kinase and the epidermal growth factor receptor in sertoli cells.
        Endocrinology. 2007; 148: 2066-2074
        • Manji H.K.
        • Drevets W.C.
        • Charney D.S.
        The cellular neurobiology of depression.
        Nature Med. 2001; 7: 541-547
        • Tabori N.E.
        • Stewart L.S.
        • Znamensky V.
        • Romeo R.D.
        • Alves S.E.
        • McEwen B.S.
        • et al.
        Ultrastructural evidence that androgen receptors are located at extranuclear sites in the rat hippocampal formation.
        Neuroscience. 2005; 130: 151-163
        • Konkle A.T.
        • McCarthy M.M.
        Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain.
        Endocrinology. 2011; 152: 223-235
        • Weiland N.G.
        • Orikasa C.
        • Hayashi S.
        • McEwen B.S.
        Distribution and hormone regulation of estrogen receptor immunoreactive cells in the hippocampus of male and female rats.
        J Comp Neurol. 1997; 388: 603-612
        • McEwen B.
        Estrogen actions throughout the brain.
        Recent Prog Horm Res. 2002; 57: 357-384
        • Barha C.K.
        • Lieblich S.E.
        • Galea L.A.
        Different forms of oestrogen rapidly upregulate cell proliferation in the dentate gyrus of adult female rats.
        J Neuroendocrinol. 2009; 21: 155-166
        • Galea L.A.
        Gonadal hormone modulation of neurogenesis in the dentate gyrus of adult male and female rodents.
        Brain Res Rev. 2008; 57: 332-341
        • Barker J.M.
        • Galea L.A.
        Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats.
        Neuroscience. 2008; 152: 888-902