Skip to main content
SpringerLink
Log in

Disruption of the CaMKII/CREB Signaling is Associated with Zinc Deficiency-Induced Learning and Memory Impairments

  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Many studies have shown that zinc deficiency not only retards growth, but also affects several brain functions, including learning and memory. However, the underlying mechanism of impaired hippocampus-dependent learning and memory under zinc deficiency is poorly understood. In this study, young mice were fed a zinc-deficient diet (0.85 ppm) for 5 weeks. Morris water maze result showed that zinc deficiency results in spatial learning impairment. We then examined whether zinc depletion-induced learning and memory defects are associated with changes in signaling molecules essential for the expression of long-term potentiation. Immunoblot results showed that the protein levels of calmodulin (CaM), phosphorylated CaM-dependent protein kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (CREB) were significantly reduced, whereas the total protein levels of CaMKII and CREB did not change in the zinc-deficient hippocampus. Thus, we provide a previously unrecognized mechanism whereby zinc deficiency impairs hippocampal learning and memory, at least in part, through disruption of the CaM/CaMKII/CREB signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Barco A, Alarcon JM, Kandel ER (2002) Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108:689–703

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Chin D, Means AR (2000) Calmodulin: a prototypical calcium sensor. Trends Cell Biol 10:322–328

    Article  PubMed  CAS  Google Scholar 

  • Cole TB, Martyanova A, Palmiter RD (2001) Removing zinc from synaptic vesicles does not impair spatial learning, memory, or sensorimotor functions in the mouse. Brain Res 891:253–265

    Article  PubMed  CAS  Google Scholar 

  • Costa-Mattioli M, Gobert D, Harding H, Herdy B, Azzi M, Bruno M, Bidinosti M, Ben Mamou C, Marcinkiewicz E, Yoshida M, Imataka H, Cuello AC, Seidah N, Sossin W, Lacaille JC, Ron D, Nader K, Sonenberg N (2005) Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 436:1166–1173

    Article  PubMed  CAS  Google Scholar 

  • De Roo M, Klauser P, Muller D (2008) LTP promotes a selective long-term stabilization and clustering of dendritic spines. PLoS Biol 6:e219

    Article  PubMed  Google Scholar 

  • Fang L, Wu J, Lin Q, Willis WD (2002) Calcium-calmodulin-dependent protein kinase II contributes to spinal cord central sensitization. J Neurosci 22:4196–4204

    PubMed  CAS  Google Scholar 

  • Fink CC, Meyer T (2002) Molecular mechanisms of CaMKII activation in neuronal plasticity. Curr Opin Neurobiol 12:293–299

    Article  PubMed  CAS  Google Scholar 

  • Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462

    Article  PubMed  CAS  Google Scholar 

  • Fukunaga K, Miyamoto E (2000) A working model of CaM kinase II activity in hippocampal long-term potentiation and memory. Neurosci Res 38:3–17

    Article  PubMed  CAS  Google Scholar 

  • Gao HL, Zheng W, Xin N, Chi ZH, Wang ZY, Chen J (2009) Zinc deficiency reduces neurogenesis accompanied by neuronal apoptosis through caspase-dependent and -independent signaling pathways. Neurotox Res 16:416–425

    Article  PubMed  CAS  Google Scholar 

  • Garry EM, Moss A, Delaney A, O’Neill F, Blakemore J, Bowen J, Husi H, Mitchell R, Grant SG, Fleetwood-Walker SM (2003) Neuropathic sensitization of behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice. Curr Biol 13:321–328

    Article  PubMed  CAS  Google Scholar 

  • Golub MS, Keen CL, Gershwin ME, Hendrickx AG (1995) Developmental zinc deficiency and behavior. J Nutr 125:2263S–2271S

    PubMed  CAS  Google Scholar 

  • Gubellini P, Ben-Ari Y, Gaiarsa JL (2005) Endogenous neurotrophins are required for the induction of GABAergic long-term potentiation in the neonatal rat hippocampus. J Neurosci 25:5796–5802

    Article  PubMed  CAS  Google Scholar 

  • Halas ES, Eberhardt MJ, Diers MA, Sandstead HH (1983) Learning and memory impairment in adult rats due to severe zinc deficiency during lactation. Physiol Behav 30:371–381

    Article  PubMed  CAS  Google Scholar 

  • Halas ES, Hunt CD, Eberhardt MJ (1986) Learning and memory disabilities in young adult rats from mildly zinc deficient dams. Physiol Behav 37:451–458

    Article  PubMed  CAS  Google Scholar 

  • Hardingham N, Glazewski S, Pakhotin P, Mizuno K, Chapman PF, Giese KP, Fox K (2003) Neocortical long-term potentiation and experience-dependent synaptic plasticity require alpha-calcium/calmodulin-dependent protein kinase II autophosphorylation. J Neurosci 23:4428–4436

    PubMed  CAS  Google Scholar 

  • Hudmon A, Schulman H (2002a) Neuronal CA2 +/calmodulin-dependent protein kinase II: the role of structure and autoregulation in cellular function. Annu Rev Biochem 71:473–510

    Article  PubMed  CAS  Google Scholar 

  • Hudmon A, Schulman H (2002b) Structure-function of the multifunctional Ca2 +/calmodulin-dependent protein kinase II. Biochem J 364:593–611

    Article  PubMed  CAS  Google Scholar 

  • Impey S, Mark M, Villacres EC, Poser S, Chavkin C, Storm DR (1996) Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 16:973–982

    Article  PubMed  CAS  Google Scholar 

  • Keller KA, Chu Y, Grider A, Coffield JA (2000) Supplementation with L-histidine during dietary zinc repletion improves short-term memory in zinc-restricted young adult male rats. J Nutr 130:1633–1640

    PubMed  CAS  Google Scholar 

  • Kida S, Josselyn SA, de Ortiz SP, Kogan JH, Chevere I, Masushige S, Silva AJ (2002) CREB required for the stability of new and reactivated fear memories. Nat Neurosci 5:348–355

    Article  PubMed  CAS  Google Scholar 

  • Lengyel I, Fieuw-Makaroff S, Hall AL, Sim AT, Rostas JA, Dunkley PR (2000) Modulation of the phosphorylation and activity of calcium/calmodulin-dependent protein kinase II by zinc. J Neurochem 75:594–605

    Article  PubMed  CAS  Google Scholar 

  • Lisman J, Schulman H, Cline H (2002) The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3:175–190

    Article  PubMed  CAS  Google Scholar 

  • Liu J, Jiang YG, Huang CY, Fang HY, Fang HT, Pang W (2008) Depletion of intracellular zinc down-regulates expression of Uch-L1 mRNA and protein, and CREB mRNA in cultured hippocampal neurons. Nutr Neurosci 11:96–102

    Article  PubMed  CAS  Google Scholar 

  • Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623

    Article  PubMed  CAS  Google Scholar 

  • Lu YM, Taverna FA, Tu R, Ackerley CA, Wang YT, Roder J (2000) Endogenous Zn(2+) is required for the induction of long-term potentiation at rat hippocampal mossy fiber-CA3 synapses. Synapse 38:187–197

    Article  PubMed  CAS  Google Scholar 

  • Marie H, Morishita W, Yu X, Calakos N, Malenka RC (2005) Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron 45:741–752

    Article  PubMed  CAS  Google Scholar 

  • Martin KC, Casadio A, Zhu H, Yaping E, Rose JC, Chen M, Bailey CH, Kandel ER (1997) Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91:927–938

    Article  PubMed  CAS  Google Scholar 

  • Matynia A, Kushner SA, Silva AJ (2002) Genetic approaches to molecular and cellular cognition: a focus on LTP and learning and memory. Annu Rev Genet 36:687–720

    Article  PubMed  CAS  Google Scholar 

  • Mayford M, Bach ME, Kandel E (1996) CaMKII function in the nervous system explored from a genetic perspective. Cold Spring Harb Symp Quant Biol 61:219–224

    PubMed  CAS  Google Scholar 

  • Meyer TE, Habener JF (1993) Cyclic adenosine 3′,5′-monophosphate response element binding protein (CREB) and related transcription-activating deoxyribonucleic acid-binding proteins. Endocr Rev 14:269–290

    PubMed  CAS  Google Scholar 

  • Miller S, Yasuda M, Coats JK, Jones Y, Martone ME, Mayford M (2002) Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36:507–519

    Article  PubMed  CAS  Google Scholar 

  • Miyamoto E (2006) Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus. J Pharmacol Sci 100:433–442

    Article  PubMed  CAS  Google Scholar 

  • Miyamoto E, Fukunaga K (1996) A role of Ca2+/calmodulin-dependent protein kinase II in the induction of long-term potentiation in hippocampal CA1 area. Neurosci Res 24:117–122

    Article  PubMed  CAS  Google Scholar 

  • Mizuno M, Yamada K, Maekawa N, Saito K, Seishima M, Nabeshima T (2002) CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning. Behav Brain Res 133:135–141

    Article  PubMed  CAS  Google Scholar 

  • Montminy MR, Gonzalez GA, Yamamoto KK (1990) Regulation of cAMP-inducible genes by CREB. Trends Neurosci 13:184–188

    Article  PubMed  CAS  Google Scholar 

  • Palmiter RD, Cole TB, Quaife CJ, Findley SD (1996) ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci USA 93:14934–14939

    Article  PubMed  CAS  Google Scholar 

  • Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W (2008) Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models. J Exp Med 205:2781–2789

    Article  PubMed  CAS  Google Scholar 

  • Sensi SL, Canzoniero LM, 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 17:9554–9564

    PubMed  CAS  Google Scholar 

  • Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861

    Article  PubMed  CAS  Google Scholar 

  • Sheng M, Thompson MA, Greenberg ME (1991) CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252:1427–1430

    Article  PubMed  CAS  Google Scholar 

  • Silva AJ, Kogan JH, Frankland PW, Kida S (1998) CREB and memory. Annu Rev Neurosci 21:127–148

    Article  PubMed  CAS  Google Scholar 

  • Smart TG, Hosie AM, Miller PS (2004) Zn2+ ions: modulators of excitatory and inhibitory synaptic activity. Neuroscientist 10:432–442

    Article  PubMed  CAS  Google Scholar 

  • Takeda A (2000) Movement of zinc and its functional significance in the brain. Brain Res Brain Res Rev 34:137–148

    Article  PubMed  CAS  Google Scholar 

  • Takeda A, Takefuta S, Okada S, Oku N (2000) Relationship between brain zinc and transient learning impairment of adult rats fed zinc-deficient diet. Brain Res 859:352–357

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Takeda A, Kanno S, Sakurada N, Ando M, Oku N (2008a) Attenuation of hippocampal mossy fiber long-term potentiation by low micromolar concentrations of zinc. J Neurosci Res 86:2906–2911

    Article  PubMed  CAS  Google Scholar 

  • Takeda A, Yamada K, Tamano H, Fuke S, Kawamura M, Oku N (2008b) Hippocampal calcium dyshomeostasis and long-term potentiation in 2-week zinc deficiency. Neurochem Int 52:241–246

    Article  PubMed  CAS  Google Scholar 

  • Tropea TF, Kosofsky BE, Rajadhyaksha AM (2008) Enhanced CREB and DARPP-32 phosphorylation in the nucleus accumbens and CREB, ERK, and GluR1 phosphorylation in the dorsal hippocampus is associated with cocaine-conditioned place preference behavior. J Neurochem 106:1780–1790

    Article  PubMed  CAS  Google Scholar 

  • Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118

    PubMed  CAS  Google Scholar 

  • Wayman GA, Lee YS, Tokumitsu H, Silva A, Soderling TR (2008) Calmodulin-kinases: modulators of neuronal development and plasticity. Neuron 59:914–931

    Article  PubMed  CAS  Google Scholar 

  • Weiss JH, Koh JY, Christine CW, Choi DW (1989) Zinc and LTP. Nature 338:212

    Article  PubMed  CAS  Google Scholar 

  • Worgotter F, Porr B (2005) Temporal sequence learning, prediction, and control: a review of different models and their relation to biological mechanisms. Neural Comput 17:245–319

    Article  PubMed  Google Scholar 

  • Xu H, Gao HL, Zheng W, Xin N, Chi ZH, Bai SL, Wang ZY (2010) Lactational zinc deficiency-induced hippocampal neuronal apoptosis by a BDNF-independent TrkB signaling pathway. Hippocampus. doi: 10.1002/hipo.20767

Download references

Acknowledgments

The study was supported by the Natural Science Foundation of China (30370452, 30770680), the Program for New Century Excellent Talents in University (NCET-04-0288), the China Postdoctoral Science Foundation (2005037008), the Research Project for Universities of the Department of Education of Liaoning (20060948), and the Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP-20060159001).

Author information

Authors and Affiliations

  1. Key Lab of Cell Biology of Ministry of Education of China, China Medical University, Bei-Er Road 92, Shenyang, 110001, People’s Republic of China

    Hui-Ling Gao, He Xu, Na Xin, Wei Zheng, Zhi-Hong Chi & Zhan-You Wang

Authors
  1. Hui-Ling Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. He Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Na Xin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhi-Hong Chi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhan-You Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhan-You Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gao, HL., Xu, H., Xin, N. et al. Disruption of the CaMKII/CREB Signaling is Associated with Zinc Deficiency-Induced Learning and Memory Impairments. Neurotox Res 19, 584–591 (2011). https://doi.org/10.1007/s12640-010-9206-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-010-9206-y

Keywords

Search

Navigation