Skip to main content

Advertisement

SpringerLink
Log in

Melatonin Attenuates Scopolamine-Induced Memory/Synaptic Disorder by Rescuing EPACs/miR-124/Egr1 Pathway

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is the most prevalent type of dementia in elderly people. There are decreased melatonin levels in the serum of AD patients, and melatonin supplements are able to reverse AD pathology and memory deficits in many animal experiments and clinical trials. However, the underlying mechanism regarding how melatonin rescues the AD-like memory/synaptic disorder remains unknown. Here, we use the Morris water maze, step-down inhibitory avoidance task, in vivo long-term potentiation recording, and Golgi staining and report that intraperitoneal injection of melatonin (1 mg/kg/day) for 14 days in rats effectively reverses the memory and synaptic impairment in scopolamine-induced amnesia, a well-recognized dementia animal model. Using real-time polymerase chain reaction and western blotting experiments, we further determined that melatonin rescues the EPACs/miR-124/Egr1 signal pathway, which is important in learning and memory, as reported recently. Our studies provide a novel underlying epigenetic mechanism for melatonin to attenuate the synaptic disorder and could benefit drug discovery in neurodegenerative diseases.

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

  1. Chang CF, Huang HJ, Lee HC, Hung KC, Wu RT, Lin AM (2012) Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and alpha-synuclein aggregation. J Pineal Res 52:312–321. doi:10.1111/j.1600-079X.2011.00945.x

    Article  PubMed  CAS  Google Scholar 

  2. Zhu LQ, Wang SH, Ling ZQ, Wang DL, Wang JZ (2004) Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat. J Pineal Res 37:71–77. doi:10.1111/j.1600-079X.2004.00136.xJPI136 [pii]

    Article  PubMed  CAS  Google Scholar 

  3. Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF (2003) Early neuropathological Alzheimer's changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 35:125–130

    Article  PubMed  CAS  Google Scholar 

  4. Ramirez-Rodriguez G, Ortiz-Lopez L, Dominguez-Alonso A, Benitez-King GA, Kempermann G (2010) Chronic treatment with melatonin stimulates dendrite maturation and complexity in adult hippocampal neurogenesis of mice. J Pineal Res 50:29–37. doi:10.1111/j.1600-079X.2010.00802.x

    Article  PubMed  Google Scholar 

  5. Dominguez-Alonso A, Ramirez-Rodriguez G, Benitez-King G (2012) Melatonin increases dendritogenesis in the hilus of hippocampal organotypic cultures. J Pineal Res 52:427–436. doi:10.1111/j.1600-079X.2011.00957.x

    Article  PubMed  CAS  Google Scholar 

  6. Gonzalez-Burgos I, Letechipia-Vallejo G, Lopez-Loeza E, Morali G, Cervantes M (2007) Long-term study of dendritic spines from hippocampal CA1 pyramidal cells, after neuroprotective melatonin treatment following global cerebral ischemia in rats. Neurosci Lett 423:162–166. doi:10.1016/j.neulet.2007.06.050

    Article  PubMed  CAS  Google Scholar 

  7. Pascual R, Bustamante C (2010) Melatonin promotes distal dendritic ramifications in layer II/III cortical pyramidal cells of rats exposed to toluene vapors. Brain Res 1355:214–220. doi:10.1016/j.brainres.2010.07.086

    Article  PubMed  CAS  Google Scholar 

  8. Saxena G, Bharti S, Kamat PK, Sharma S, Nath C (2009) Melatonin alleviates memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats. Pharmacol Biochem Behav 94:397–403. doi:10.1016/j.pbb.2009.09.022

    Article  PubMed  Google Scholar 

  9. Shen YX, Wei W, Yang J, Liu C, Dong C, Xu SY (2001) Improvement of melatonin to the learning and memory impairment induced by amyloid beta-peptide 25–35 in elder rats. Acta Pharmacol Sin 22:797–803

    PubMed  CAS  Google Scholar 

  10. Yang X et al (2010) Melatonin ameliorates Alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A. J Psychopharmacol 25:1118–1125. doi:10.1177/0269881110367723

    Article  PubMed  Google Scholar 

  11. Agrawal R, Tyagi E, Shukla R, Nath C (2008) Effect of insulin and melatonin on acetylcholinesterase activity in the brain of amnesic mice. Behav Brain Res 189:381–386. doi:10.1016/j.bbr.2008.01.015

    Article  PubMed  CAS  Google Scholar 

  12. Schratt G (2009) microRNAs at the synapse. Nat Rev Neurosci 10:842–849. doi:10.1038/nrn2763

    Article  PubMed  CAS  Google Scholar 

  13. Lee SE, Kim SJ, Youn JP, Hwang SY, Park CS, Park YS (2011) MicroRNA and gene expression analysis of melatonin-exposed human breast cancer cell lines indicating involvement of the anticancer effect. J Pineal Res 51:345–352. doi:10.1111/j.1600-079X.2011.00896.x

    Article  PubMed  CAS  Google Scholar 

  14. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60

    Article  PubMed  CAS  Google Scholar 

  15. Yin YY et al (2010) Acetyl-l-carnitine attenuates okadaic acid induced tau hyperphosphorylation and spatial memory impairment in rats. J Alzheimers Dis 19:735–746. doi:10.3233/JAD-2010-1272

    PubMed  CAS  Google Scholar 

  16. Zhu LQ et al (2007) Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments. J Neurosci 27:12211–12220. doi:10.1523/JNEUROSCI.3321-07.2007

    Article  PubMed  CAS  Google Scholar 

  17. Segal M (2005) Dendritic spines and long-term plasticity. Nat Rev Neurosci 6:277–284. doi:10.1038/nrn1649

    Article  PubMed  CAS  Google Scholar 

  18. Hsieh MT, Hsieh CL, Lin LW, Wu CR, Huang GS (2003) Differential gene expression of scopolamine-treated rat hippocampus-application of cDNA microarray technology. Life Sci 73:1007–1016

    Article  PubMed  CAS  Google Scholar 

  19. Roy D, Belsham DD (2002) Melatonin receptor activation regulates GnRH gene expression and secretion in GT1-7 GnRH neurons. Signal transduction mechanisms. J Biol Chem 277:251–258. doi:10.1074/jbc.M108890200 M108890200 [pii]

    Article  PubMed  CAS  Google Scholar 

  20. Yang Y et al (2012) EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation. Neuron 73:774–788. doi:10.1016/j.neuron.2012.02.003

    Article  PubMed  CAS  Google Scholar 

  21. Verloes R, Scotto AM, Gobert J, Wulfert E (1988) Effects of nootropic drugs in a scopolamine-induced amnesia model in mice. Psychopharmacol (Berl) 95:226–230

    Article  CAS  Google Scholar 

  22. Brouillette J, Young D, During MJ, Quirion R (2007) Hippocampal gene expression profiling reveals the possible involvement of Homer1 and GABA(B) receptors in scopolamine-induced amnesia. J Neurochem 102:1978–1989. doi:10.1111/j.1471-4159.2007.04666.x

    Article  PubMed  CAS  Google Scholar 

  23. Laurent AC, Breckler M, Berthouze M, Lezoualc'h F (2012) Role of Epac in brain and heart. Biochem Soc Trans 40:51–57. doi:10.1042/BST20110642

    Article  PubMed  CAS  Google Scholar 

  24. Ostroveanu A, van der Zee EA, Eisel UL, Schmidt M, Nijholt IM (2009) Exchange protein activated by cyclic AMP 2 (Epac2) plays a specific and time-limited role in memory retrieval. Hippocampus 20:1018–1026. doi:10.1002/hipo.20700

    Article  Google Scholar 

  25. Ouyang M, Zhang L, Zhu JJ, Schwede F, SA T (2008) Epac signaling is required for hippocampus-dependent memory retrieval. Proc Natl Acad Sci USA 105:11993–11997

    Article  PubMed  CAS  Google Scholar 

  26. Ma N, Abel T, Hernandez PJ (2009) Exchange protein activated by cAMP enhances long-term memory formation independent of protein kinase A. Learn Mem 16:367–370. doi:10.1101/lm.1231009

    Article  PubMed  CAS  Google Scholar 

  27. Gelinas JN, Banko JL, Peters MM, Klann E, Weeber EJ, Nguyen PV (2008) Activation of exchange protein activated by cyclic-AMP enhances long-lasting synaptic potentiation in the hippocampus. Learn Mem 15:403–411. doi:10.1101/lm.830008

    Article  PubMed  CAS  Google Scholar 

  28. Ster J et al (2009) Epac mediates PACAP-dependent long-term depression in the hippocampus. J Physiol 587:101–113. doi:10.1113/jphysiol.2008.157461

    Article  PubMed  CAS  Google Scholar 

  29. Gekel I, Neher E (2008) Application of an Epac activator enhances neurotransmitter release at excitatory central synapses. J Neurosci 28:7991–8002. doi:10.1523/JNEUROSCI.0268-08.2008

    Article  PubMed  CAS  Google Scholar 

  30. Woolfrey KM et al (2009) Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat Neurosci 12:1275–1284. doi:10.1038/nn.2386

    Article  PubMed  CAS  Google Scholar 

  31. Enserink JM et al (2004) The cAMP-Epac-Rap1 pathway regulates cell spreading and cell adhesion to laminin-5 through the alpha3beta1 integrin but not the alpha6beta4 integrin. J Biol Chem 279:44889–44896. doi:10.1074/jbc.M404599200 M404599200 [pii]

    Article  PubMed  CAS  Google Scholar 

  32. Lopez De Jesus M et al (2006) Cyclic AMP-dependent and Epac-mediated activation of R-Ras by G protein-coupled receptors leads to phospholipase D stimulation. J Biol Chem 281:21837–21847. doi:10.1074/jbc.M604156200

    Article  PubMed  Google Scholar 

  33. Makeyev EV, Zhang J, Carrasco MA, Maniatis T (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol Cell 27:435–448. doi:10.1016/j.molcel.2007.07.015

    Article  PubMed  CAS  Google Scholar 

  34. Clokie SJ, Lau P, Kim HH, Coon SL, Klein D (2012) Micro RNAs in the pineal gland: mir-483 regulates melatonin synthesis by targeting arylalkylamine N-acetyltransferase. J Biol Chem. doi:10.1074/jbc.M112.356733

  35. Masilamoni JG et al (2008) The neuroprotective role of melatonin against amyloid beta peptide injected mice. Free Radic Res 42:661–673. doi:10.1080/10715760802277388

    Article  PubMed  CAS  Google Scholar 

  36. Jeong JK, Moon MH, Lee YJ, Seol JW, Park SY (2012) Melatonin-induced autophagy protects against human prion protein-mediated neurotoxicity. J Pineal Res. doi:10.1111/j.1600-079X.2012.00980.x

  37. Lee EJ et al (2005) Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia. J Pineal Res 38:42–52. doi:10.1111/j.1600-079X.2004.00173.x

    Article  PubMed  CAS  Google Scholar 

  38. Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S (2003) Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nihon Med Sch 70:334–341

    Article  Google Scholar 

  39. Uchida K, Okamoto N, Ohara K, Morita Y (1996) Daily rhythm of serum melatonin in patients with dementia of the degenerate type. Brain Res 717:154–159

    Article  PubMed  CAS  Google Scholar 

  40. Crozier RA, Bi C, Han YR, Plummer MR (2008) BDNF modulation of NMDA receptors is activity dependent. J Neurophysiol 100:3264–3274. doi:10.1152/jn.90418.2008

    Article  PubMed  CAS  Google Scholar 

  41. Evans GJ, Cousin MA (2007) Activity-dependent control of slow synaptic vesicle endocytosis by cyclin-dependent kinase 5. J Neurosci 27:401–411. doi:10.1523/JNEUROSCI.3809-06.2007

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (30971478, 91132725, 31201011), the New Century Excellent Talent of Education Ministry (NCET-10-0421), the Ministry of Science and Technology of China (2011DFG33250), the New Investigator Research Grant of Alzheimer’s Association (NIRG-11-205737), and the Fundamental Research Funds for the Central Universities, HUST, (nos. 0118510011 and 0118510019).

Author information

Authors and Affiliations

  1. Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China

    Xiong Wang, Zhi-Hao Wang, Yuan-Yuan Wu, Hui Tang, Lu Tan, Xiang Wang, Xin-Ya Gao, Yan-Si Xiong, Jian-Zhi Wang & Ling-Qiang Zhu

  2. Department of Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    Dan Liu

  3. Key Laboratory of Neurological Diseases, Ministry of Education, Wuhan, China

    Dan Liu, Jian-Zhi Wang & Ling-Qiang Zhu

Authors
  1. Xiong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-Hao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuan-Yuan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lu Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xin-Ya Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan-Si Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jian-Zhi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ling-Qiang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Dan Liu or Ling-Qiang Zhu.

Additional information

Xiong Wang and Zhi-Hao Wang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, X., Wang, ZH., Wu, YY. et al. Melatonin Attenuates Scopolamine-Induced Memory/Synaptic Disorder by Rescuing EPACs/miR-124/Egr1 Pathway. Mol Neurobiol 47, 373–381 (2013). https://doi.org/10.1007/s12035-012-8355-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-012-8355-9

Keywords

Search

Navigation