Abstract
Zinc is released from glutamatergic (zincergic) neuron terminals in the brain, followed by the increase in Zn2+ concentration in the intracellular (cytosol) compartment as well as that in the extracellular compartment. Intracellular Zn2+ concentration mainly increases through calcium-permeable channels and serves as Zn2+ signal as well as extracellular Zn2+ concentration. Hippocampal Zn2+ signaling may participate in synaptic plasticity such as long-term potentiation and cognitive function. On the other hand, subclinical zinc deficiency is common in the old who might be more susceptible to depression. Zinc deficiency causes abnormal glucocorticoid secretion and increases depression-like behavior in animals. Neuropsychological symptoms are observed prior to the decrease in Zn2+ signal in the hippocampus under zinc deficiency. This paper summarizes that hippocampal Zn2+ signaling serves to maintain healthy brain and that glucocorticoid signaling, which is responsive to zinc homeostasis in the living body, is linked to the pathophysiology of depression.
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References
Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462
Prasad AS (2008) Zinc in human health: effect of zinc on immune cells. Mol Med 14:353–357
Brown KH, Wuehler SE, Peerson JM (2001) The importance of zinc in human nutrition and estimation of the blobal prevalence of zinc deficiency. Food Nutr Bull 22:113–125
King JC, Shames DM, Woodhouse LR (2000) Zinc homeostasis in humans. J Nutr 130:1360S–1366S
Vallee BL, Falchuk KH (1993) The biological basis of zinc physiology. Physiol Rev 73:79–118
Sandstead HH, Frederickson CJ, Penland JG (2000) History of zinc as related to brain function. J Nutr 130:496S–502S
Burdette SC, Lippard SJ (2003) Meeting of the minds: metalloneurochemistry. Proc Natl Acad Sci USA 100:3605–3610
Markesbery WR, Ehmann WD, Alauddin M, Hossain TIM (1984) Brain trace element concentrations in aging. Neurobiol Aging 5:19–28
Weiss JH, Sensi SL, Koh JY (2000) Zn(2+): a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci 21:395–401
Hershey CO, Hershey LA, Varnes A, Vibhakar SD, Lavin P, Strain WH (1983) Cerebrospinal fluid trace element content in dementia: clinical, radiologic, and pathologic correlations. Neurology 33:1350–1353
Takeda A, Akiyama T, Sawashita J, Okada S (1994) Brain uptake of trace metals, zinc and manganese, in rats. Brain Res 640:341–344
Takeda A (2000) Movement of zinc and its functional significance in the brain. Brain Res Rev 34:137–148
Takeda A (2001) Zinc homeostasis and functions of zinc in the brain. Biometals 14:343–352
Takeda A, Sawashita J, Okada S (1995) Biological half-lives of zinc and manganese in rat brain. Brain Res 695:53–58
Capasso M, Jeng JM, Malavolta M, Mocchegiani E, Sensi SL (2005) Zinc dyshomeostasis: a key modulator of neuronal injury. J Alzheimers Dis 8:93–108
Mocchegiani E, Bertoni-Freddari C, Marcellini F, Malavolta M (2005) Brain, aging and neurodegeneration: role of zinc ion availability. Prog Neurobiol 75:367–390
Frazzini V, Rockabrand E, Mocchegiani E, Sensi SL (2006) Oxidative stress and brain aging: is zinc the link? Biogerontology 7:307–314
Bressler JP, Olivi L, Cheong JH, Kim Y, Maerten A, Bannon D (2007) Metal transporters in intestine and brain: their involvement in metal-associated neurotoxicities. Hum Exp Toxicol 26:221–229
Frederickson CJ (1989) Neurobiology of zinc and zinc-containing neurons. Int Rev Neurobiol 31:145–238
Frederickson CJ, Bush AI (2001) Synaptically released zinc: physiological functions and pathological effects. Biometals 14:353–366
Frederickson CJ, Moncrieff DW (1994) Zinc-containing neurons. Biol Signals 3:127–139
Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD (1999) Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc Natl Acad Sci USA 96(4):1716–1721
Valente T, Auladell C (2002) Developmental expression of ZnT3 in mouse brain: correlation between the vesicular zinc transporter protein and chelatable vesicular zinc (CVZ) cells. Glial and neuronal CVZ cells interact. Mol Cell Neurosci 21:189–204
Valente T, Auladell C, Pérez-Clausell J (2002) Postnatal development of zinc-rich terminal fields in the brain of the rat. Exp Neurol 174:215–229
Frederickson CJ, Giblin LJ, Krezel A, McAdoo DJ, Muelle RN, Zeng Y, Balaji RV, Masalha R, Thompson RB, Fierke CA, Sarvey JM, Valdenebro M, Prough DS, Zornow MH (2006) Concentrations of extracellular free zinc (pZn)e in the central nervous system during simple anesthetization, ischemia and reperfusion. Exp Neurol 198:285–293
Sensi SL, Canzoniero LMT, Yu SP, Ying HS, Koh JY, Kerchner GA, Choi DW (1997) Measurement of intracellular free zinc in living cortical neurons: routes of entry. J Neurosci 15:9554–9564
Minami A, Sakurada N, Fuke S, Kikuchi K, Nagano T, Oku N, Takeda A (2006) Inhibition of presynaptic activity by zinc released from mossy fiber terminals during tetanic stimulation. J Neurosci Res 83:167–176
Sensi SL, Ton-That D, Sullivan PG, Jonas EA, Gee KR, Kaczmarek LK, Weiss JH (2003) Modulation of mitochondrial function by endogenous Zn2+ pools. Proc Natl Acad Sci USA 100:6157–6162
Maret W (2006) Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid Redox Signal 8:1419–1441
Krezel A, Hao Q, Maret W (2007) The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling. Arch Biochem Biophys 463:188–200
Bird CM, Burgess N (2008) The hippocampus and memory: insights from spatial processing. Nat Rev Neurosci 9:182–194
Frederickson CJ, Danscher G (1990) Zinc-containing neurons in hippocampus and related CNS structures. Prog Brain Res 83:71–84
Smart TG, Xie X, Krishek BJ (1994) Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc. Prog Neurobiol 42:393–441
Takeda A, Tamano H (2009) Insight into zinc signaling from dietary zinc deficiency. Brain Res Rev 62:33–34
Nakashima AS, Dyck RH (2009) Zinc and cortical plasticity. Brain Res Rev 59:347–373
Takeda A, Tamano H (2010) Zinc signaling through glucocorticoid and glutamate signaling in stressful circumstances. J Neurosci Res 88:3002–3010
Idei M, Miyake K, Horiuchi Y, Tabe Y, Miyake N, Ikeda N, Miida T (2010) Serum zinc concentration decreases with age and is associated with anemia in middle-aged and elderly people. Rinsho Byori 58:205–210
Blazer DG 2nd, Hybels CF (2005) Origins of depression in later life. Psychol Med 35:1241–1252
Nakatani N, Aburatani H, Nishimura K, Semba J, Yoshikawa T (2004) Comprehensive expression analysis of a rat depression model. Pharmacogenomics J 4:114–126
Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, Reddy R, Aschner M, Lewis DA, Mirnics K (2010) Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry (in press).
Sowa-Kućma M, Kowalska M, Szlósarczyk M, Gołembiowska K, Opoka W, Baś B, Pilc A, Nowak G (2010) Chronic treatment with zinc and antidepressants induces enhancement of presynaptic/extracellular zinc concentration in the rat prefrontal cortex. Amino Acids (in press).
Takeda A, Minami A, Seki Y, Oku N (2003) Inhibitory function of zinc against excitation of hippocampal glutamatergic neurons. Epilepsy Res 57:169–174
Takeda A, Minami A, Seki Y, Oku N (2004) Differential effects of zinc on glutamatergic and GABAergic neurotransmitter systems in the hippocampus. J Neurosci Res 75:225–229
Cohen-Kfir E, Lee W, Eskandari S, Nelson N (2005) Zinc inhibition of gamma-aminobutyric acid transporter 4 (GAT4) reveals a link between excitatory and inhibitory neurotransmission. Proc Natl Acad Sci USA 102:6154–6159
Takeda A, Fuke S, Minami A, Oku N (2007) Role of zinc influx via AMPA/kainate receptor activation in metabotropic glutamate receptor-mediated calcium release. J Neurosci Res 85:1310–1317
Jia Y, Jeng JM, Sensi S, Weiss JH (2002) Zn2+ currents are mediated by calcium-permeable AMPA/kainite channels in cultured murine hippocampal neurons. J Physiol Lond 543:35–48
Takeda A, Fuke S, Tsutsumi W, Oku N (2007) Negative modulation of presynaptic activity by zinc released from Schaffer collaterals. J Neurosci Res 85:3666–3672
Ando M, Oku N, Takeda A (2010) Zinc-mediated attenuation of hippocampal mossy fiber long-term potentiation induced by forskolin. Neurochem Int 57:608–614
Quinta-Ferreira ME, Matias CM (2004) Hippocampal mossy fiber calcium transients are maintained during long-term potentiation and are inhibited by endogenous zinc. Brain Res 1004:52–60
Quinta-Ferreira ME, Matias CM (2005) Tetanically released zinc inhibits hippocampal mossy fiber calcium, zinc and synaptic responses. Brain Res 1047:1–9
Bancila V, Nikonenko I, Dunant Y, Bloc A (2004) Zinc inhibits glutamate release via activation of pre-synaptic KATP channels and reduces ischaemic damage in rat hippocampus. J Neurochem 90:1243–1250
Kapur A, Yeckel MF, Grey R, Johnston D (1998) L-type calcium channels are required for one form of hippocampal mossy fiber LTP. J Neurophysiol 79:2181–2190
Neves G, Cooke SF, Bliss TV (2008) Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci 9:65–75
Daumas S, Halley H, Lassalle JM (2004) Disruption of hippocampal CA3 network: effects on episodic-like memory processing in C57BL/6J mice. Eur J Neurosci 20:597–600
Ueno S, Tsukamoto M, Hirano T, Kikuchi K, Yamada MK, Nishiyama N, Nagano T, Matsuki N, Ikegaya Y (2002) Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-d-aspartate receptor activity in hippocampal CA3 circuits. J Cell Biol 158:215–220
Vogt K, Mellor J, Tong G, Nicoll R (2000) The actions of synaptically released zinc at hippocampal mossy fiber synapses. Neuron 26:187–196
Takeda A, Kanno S, Sakurada N, Ando M, Oku N (2008) Attenuation of hippocampal mossy fiber long-term potentiation by low micromolar concentrations of zinc. J Neurosci Res 86:2909–2911
Klein C, Sunahara RK, Hudson TY, Heyduk T, Howlett AC (2002) Zinc inhibition of cAMP signaling. J Biol Chem 277:11859–11865
Izumi Y, Auberson YP, Zorumski CF (2006) Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors. J Neurosci 26:7181–7188
Takeda A, Fuke S, Ando M, Oku N (2009) Positive modulation of long-term potentiation at hippocampal CA1 synapses by low micromolar concentrations of zinc. Neuroscience 158:585–591
Takeda A, Iwaki H, Ando M, Itagaki K, Suzuki M, Oku N (2010) Zinc differentially acts on components of long-term potentiation at hippocampal CA1 synapse. Brain Res 1323:59–64
Zola-Morgan SM, Squire LR (1990) The primate hippocampal formation: evidence for a time-limited role in memory storage. Science 250:288–290
Lavenex P, Amaral DG (2000) Hippocampal-neocortical interaction: a hierarchy of associativity. Hippocampus 10:420–430
de Curtis M, Paré D (2004) The rhinal cortices: a wall of inhibition between the neocortex and the hippocampus. Prog Neurobiol 74:101–110
Howland JG, Wang YT (2008) Synaptic plasticity in learning and memory: stress effects in the hippocampus. Prog Brain Res 169:145–158
Takeda A, Takada S, Ando M, Itagaki K, Tamano H, Suzuki M, Iwaki H, Oku N (2010) Impairment of recognition memory and hippocampal long-term potentiation after acute exposure to clioquinol. Neuroscience 171:443–450
Lauri SE, Bortolotto ZA, Nistico R, Bleakman D, Ornstein PL, Lodge D, Isaac JTR, Collingridge GL (2003) A role for Ca2+ stores in kainate receptor-dependent synaptic facilitation and LTP at mossy fiber synapses in the hippocampus. Neuron 39:327–341
Rodriguez-Moreno A, Sihra TS (2004) Presynaptic kainate receptor facilitation of glutmate release involves protein kinase A in the rat hippocampus. J Physiol 557:733–745
Koizumi S, Fujishita K, Inoue K (2005) Regulation of cell-to-cell communication mediated by astrocytic ATP in the CNS. Purinergic Signal 1:211–217
Domingues AM, Taylor M, Fern R (2010) Glia as transmitter sources and sensors in health and disease. Neurochem Int 57:359–366
Suh SW, Aoyama K, Alano CC, Anderson CM, Hamby AM, Swanson RA (2007) Zinc inhibits astrocyte glutamate uptake by activation of poly(ADP-ribose) polymerase-1. Mol Med 13:344–349
Takeda A, Minami A, Sakurada N, Nakajima S, Oku N (2007) Response of hippocampal mossy fiber zinc to excessive glutamate release. Neurochem Int 50:322–327
Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW (1996) The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 272:1013–1016
Choi DW, Koh JY (1998) Zinc and brain injury. Annu Rev Neurosci 21:347–375
Lee JM, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399:A7–A14
Sensi SL, Jeng JM (2004) Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic neuronal injury. Curr Mol Med 4:87–111
Noh KM, Yokota H, Mashiko T, Castillo PE, Zukin RS, Bennett MV (2005) Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death. Proc Natl Acad Sci USA 102:12230–12235
Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA (2007) Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest 117:910–918
Côté A, Chiasson M, Peralta MR 3rd, Lafortune K, Pellegrini L, Tóth K (2005) Cell type-specific action of seizure-induced intracellular zinc accumulation in the rat hippocampus. J Physiol 566:821–837
Lavoie N, Peralta MR 3rd, Chiasson M, Lafortune K, Pellegrini L, Seress L, Tóth K (2007) Extracellular chelation of zinc does not affect hippocampal excitability and seizure-induced cell death in rats. J Physiol 578:275–289
Takeda A, Itoh H, Tamano H, Oku N (2009) High K+-induced increase in extracellular glutamate in zinc deficiency and endogenous zinc action. J Health Sci 55:405–412
Lee AL, Ogle WO, Sapolsky RM (2002) Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord 4:117–128
Kim JJ, Yoon KS (1998) Stress: metaplastic effects in the hippocampus. Trends Neurosci 21:505–509
McEwen BS (1999) Stress and hippocampal plasticity. Ann Rev Neurosci 22:105–122
Garcia R (2001) Stress, hippocampal plastivity, and spatial learning. Synapse 40:180–183
Kim JJ, Song EY, Kosten TA (2006) Stress effects in the hippocampus: synaptic plasticity and memory. Stress 9:1–11
Takeda A, Hirate M, Tamano H, Nishibaba D, Oku N (2003) Susceptibility to kainate-induced seizures under dietary zinc deficiency. J Neurochem 85:1575–1580
Takeda A, Hirate M, Tamano H, Oku N (2003) Zinc movement in the brain under kainite-induced seizures. Epilepsy Res 54:123–129
Takeda A, Sakurada N, Kanno S, Minami A, Oku N (2006) Response of extracelluar zinc in the ventral hippocampus against novelty stress. J Neurochem 99:670–676
Takeda A, Ando M, Kanno S, Oku N (2009) Unique response of zinc in the hippocampus to behavioral stress and attenuation of subsequent mossy fiber long-term potentiation. Neurotoxicology 30:712–717
Takeda A, Tamano H, Oku N (2005) Involvement of unusual glutamate release in kainate-induced seizures in zinc-deficient adult rats. Epilepsy Res 66:137–143
Takeda A, Sakurada N, Ando M, Kanno S, Oku N (2009) Facilitation of zinc influx via AMPA/kainate receptor activation in the hippocampus. Neurochem Int 55:376–382
Takeda A, Suzuki M, Tamano H, Ando M, Oku N (2010) Differential effects of zinc influx via AMPA/kainate receptor activation on subsequent induction of hippocampal CA1 LTP components. Brain Res 1354:188–195
DeCarolis NA, Eisch AJ (2010) Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation. Neuropharmacology 58:884–893
Suh SW, Won SJ, Hamby AM, Yoo BH, Fan Y, Sheline CT, Tamano H, Takeda A, Liu J (2009) Decreased brain zinc availability reduces hippocampal neurogenesis in mice and rats. J Cereb Blood Flow Metab 29:1579–1588
Whiteford HA, Peabody CA, Thiemann S, Kraemer HC, Csernansky JG, Berger PA (1987) The effect of age on baseline and postdexamethasone cortisol levels in major depressive disorder. Biol Psychiatry 22:1029–1032
Starkman MN, Gebarski SS, Berent S, Schteingart DE (1992) Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 32:756–765
Seed JA, Dixon RA, McCluskey SE, Young AH (2000) Basal activity of the hypothalamic-pituitary-adrenal axis and cognitive function in anorexia nervosa. Eur Arch Psychiatry Clin Neurosci 250:11–15
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci USA 93:3908–3913
Sheline YI, Sanghavi M, Mintun MA, Gado MH (1999) Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci 19:5034–5043
Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000) Hippocampal volume reduction in major depression. Am J Psychiatry 157:115–118
O'Brien JT, Ames D, Schweitzer I, Colman P, Desmond P, Tress B (1996) Clinical and magnetic resonance imaging correlates of hypothalamic-pituitary-adrenal axis function in depression and Alzheimer's disease. Br J Psychiatry 168:679–687
Kawata M, Yuri K, Ozawa H, Nishi M, Ito T, Hu Z, Lu H, Yoshida M (1998) Steroid hormones and their receptors in the brain. J Steroid Biochem Mol Biol 65:273–280
Maes M, D'Haese PC, Scharpé S, D'Hondt P, Cosyns P, De Broe ME (1994) Hypozincemia in depression. J Affect Disord 31:135–140
Maes M, De Vos N, Demedts P, Wauters A, Neels H (1999) Lower serum zinc in major depression in relation to changes in serum acute phase proteins. J Affect Disord 56:189–194
Maes M, Vandoolaeghe E, Neels H, Demedts P, Wauters A, Meltzer HY, Carlo A, Roger D (1997) Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness. Biol Psychiatry 42:349–358
Siwek M, Dudek D, Paul IA, Sowa-Kućma M, Zieba A, Popik P, Pilc A, Nowak G (2009) Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study. J Affect Disord 118:187–195
Siwek M, Dudek D, Schlegel-Zawadzka M, Morawska A, Piekoszewski W, Opoka W, Zięba A, Pilc A, Popik P, Nowak G (2010) Serum zinc level in depressed patients during zinc supplementation of imipramine treatment. J Affect Disord (in press)
Takeda A, Tamano H, Kan F, Itoh H, Oku N (2007) Anxiety-like behavior of young rats after 2-week zinc deprivation. Behav Brain Res 177:1–6
Takeda A, Tamano H, Kan F, Hanajima T, Yamada K, Oku N (2008) Enhancement of social isolation-induced aggressive behavior of young mice by zinc deficiency. Life Sci 82:909–914
Whittle N, Lubec G, Singewald N (2009) Zinc deficiency induces enhanced depression-like behaviour and altered limbic activation reversed by antidepressant treatment in mice. Amino Acids 36:147–158
Tassabehji NM, Corniola RS, Alshingiti A, Levenson CW (2008) Zinc deficiency induces depression-like symptoms in adult rats. Physiol Behav 95:365–369
Tamano H, Kan F, Kawamura M, Oku N, Takeda A (2009) Behavior in the forced swim test and neurochemical changes in the hippocampus in young rats after 2-week zinc deprivation. Neurochem Int 55:536–541
Takeda A, Hirate M, Tamano H, Oku N (2003) Release of glutamate and GABA in the hippocampus under zinc deficiency. J Neurosci Res 72:537–542
Takeda A, Itoh H, Tamano H, Oku N (2006) Responsiveness to kainate in young rats after 2-week zinc deprivation. Biometals 19:565–572
Watanabe M, Tamano H, Kikuchi T, Takeda A (2010) Susceptibility to stress in young rats after 2-week zinc deprivation. Neurochem Int 56:410–416
Takeda A, Sakurada N, Kanno S, Ando M, Oku N (2008) Vulnerability to seizures induced by potassium dyshomeostasis in the hippocampus in aged rats. J Health Sci 54:37–42
Mocchegiani E, Giacconi R, Cipriano C, Muti E, Gasparini N, Malavolta M (2004) Are zinc-bound metallothionein isoforms (I + II and III) involved in impaired thymulin production and thymic involution during ageing? Immun Ageing 1:5
Ricci A, Ramacci MT, Ghirardi O, Amenta F (1989) Age-related changes of the mossy fibre system in rat hippocampus: effect of long term acetyl-l-carnitine treatment. Arch Gerontol Geriatr 8:63–71
Barili P, Fringuelli C, Ricci A, Rossodivita I, Sabbatini M (1997) Age-related changes of sulphide-silver staining in the rat hippocampus. Mech Ageing Dev 99:83–94
Landfield PW, Eldridge JC (1994) Evolving aspects of the glucocorticoid hypothesis of brain aging: hormonal modulation of neuronal calcium homeostasis. Neurobiol Aging 15:579–588
Ferrari E, Casarotti D, Muzzoni B, Albertelli N, Cravello L, Fioravanti M, Solerte SB, Magri F (2001) Age-related changes of the adrenal secretory pattern: possible role in pathological brain aging. Brain Res Brain Res Rev 37:294–300
Billard JM (2006) Ageing, hippocampal synaptic activity and magnesium. Magnes Res 19:199–215
Foster TC (2007) Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell 6:319–325
Takeda A, Yamada K, Tamano H, Fuke S, Kawamura M, Oku N (2008) Hippocampal calcium dyshomeostasis and long-term potentiation in 2-week zinc deficiency. Neurochem Int 52:241–246
Takeda A, Itoh H, Nagayoshi A, Oku N (2009) Abnormal calcium mobilization in hippocampal slices of epileptic animals fed a zinc-deficient diet. Epilepsy Res 83:73–80
Gregus A, Wintink AJ, Davis AC, Kalynchuk LE (2005) Effect of repeated corticosterone injections and restraint stress on anxiety and depression-like behavior in male rats. Behav Brain Res 156:105–114
Johnson SA, Fournier NM, Kalynchuk LE (2006) Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res 168:280–288
Zhao Y, Ma R, Shen J, Su H, Xing D, Du L (2008) A mouse model of depression induced by repeated corticosterone injections. Eur J Pharmacol 581:113–120
Mann JJ, Apter A, Bertolote J, Beautrais A, Currier D, Haas A, Hegerl U, Lonnqvist J, Malone K, Marusic A, Mehlum L, Patton G, Phillips M, Rutz W, Rihmer Z, Schmidtke A, Shaffer D, Silverman M, Takahashi Y, Varnik A, Wasserman D, Yip P, Hendin H (2005) Suicide prevention strategies: a systematic review. JAMA 294:2064–2074
Abreu LN, Lafer B, Baca-Garcia E, Oquendo MA (2009) Suicidal ideation and suicide attempts in bipolar disorder type I: an update for the clinician. Rev Bras Psiquiatr 31:271–280
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Takeda, A. Zinc Signaling in the Hippocampus and Its Relation to Pathogenesis of Depression. Mol Neurobiol 44, 166–174 (2011). https://doi.org/10.1007/s12035-010-8158-9
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DOI: https://doi.org/10.1007/s12035-010-8158-9