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Hippocampus-dependent cognitive enhancement induced by systemic gintonin administration

  • Kim, Sungmin (Department of Biological Sciences, College of Bioscience and Biotechnology, Konkuk University) ;
  • Kim, Min-Soo (Department of Biological Sciences, College of Bioscience and Biotechnology, Konkuk University) ;
  • Park, Kwanghoon (Department of Biological Sciences, College of Bioscience and Biotechnology, Konkuk University) ;
  • Kim, Hyeon-Joong (Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University) ;
  • Jung, Seok-Won (Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University) ;
  • Nah, Seung-Yeol (Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University) ;
  • Han, Jung-Soo (Department of Biological Sciences, College of Bioscience and Biotechnology, Konkuk University) ;
  • Chung, ChiHye (Department of Biological Sciences, College of Bioscience and Biotechnology, Konkuk University)
  • Received : 2015.04.23
  • Accepted : 2015.05.04
  • Published : 2016.01.15

Abstract

Background: A number of neurological and neurodegenerative diseases share impaired cognition as a common symptom. Therefore, the development of clinically applicable therapies to enhance cognition has yielded significant interest. Previously, we have shown that activation of lysophosphatidic acid receptors (LPARs) via gintonin application potentiates synaptic transmission by the blockade of $K^+$ channels in the mature hippocampus. However, whether gintonin may exert any beneficial impact directly on cognition at the neural circuitry level and the behavioral level has not been investigated. Methods: In the current study, we took advantage of gintonin, a novel LPAR agonist, to investigate the effect of gintonin-mediated LPAR activation on cognitive performances. Hippocampus-dependent fear memory test, synaptic plasticity in the hippocampal brain slices, and quantitative analysis on synaptic plasticity-related proteins were used. Results: Daily oral administration of gintonin for 1 wk significantly improved fear memory retention in the contextual fear-conditioning test in mice.We also found that oral administration of gintonin for 1 wk increased the expression of learning and memory-related proteins such as phosphorylated cyclic adenosine monophosphate-response element binding (CREB) protein and brain-derived neurotrophic factor (BDNF). In addition, prolonged gintonin administration enhanced long-term potentiation in the hippocampus. Conclusion: Our observations suggest that the systemic gintonin administration could successfully improve contextual memory formation at the molecular and synaptic levels as well as the behavioral level. Therefore, oral administration of gintonin may serve as an effective noninvasive, nonsurgical method of enhancing cognitive functions.

Keywords

References

  1. Lee YS, Silva AJ. The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 2009;10:126-40. https://doi.org/10.1038/nrn2572
  2. Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, Mutoh T, Lin ME, Teo ST, Park KE, Mosley AN, et al. LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol 2010;50:157-86. https://doi.org/10.1146/annurev.pharmtox.010909.105753
  3. Pilpel Y, Segal M. The role of LPA1 in formation of synapses among cultured hippocampal neurons. J Neurochem 2006;97:1379-92. https://doi.org/10.1111/j.1471-4159.2006.03825.x
  4. Dash PK, Orsi SA, Moody M, Moore AN. A role for hippocampal Rho-ROCK pathway in long-term spatial memory. Biochem Biophys Res Commun 2004;322:893-8. https://doi.org/10.1016/j.bbrc.2004.08.004
  5. Park H, Kim S, Rhee J, Kim HJ, Han JS, Nah SY, Chung C. Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses. J Neurophysiol 2015;113:1493-500. https://doi.org/10.1152/jn.00667.2014
  6. Hwang SH, Shin TJ, Choi SH, Cho HJ, Lee BH, Pyo MK, Lee JH, Kang J, Kim HJ, Park CW, et al. Gintonin, newly identified compounds from ginseng, is novel lysophosphatidic acids-protein complexes and activates G protein-coupled lysophosphatidic acid receptors with high affinity. Mol Cells 2012;33:151-62. https://doi.org/10.1007/s10059-012-2216-z
  7. Pyo MK, Choi SH, Shin TJ, Hwang SH, Lee BH, Kang J, Kim HJ, Lee SH, Nah SY. A simple method for the preparation of crude gintonin from ginseng root, stem, and leaf. J Ginseng Res 2011;35:209-18. https://doi.org/10.5142/jgr.2011.35.2.209
  8. Nah SY. Gintonin: a novel ginseng-derived ligand that targets G proteincoupled lysophosphatidic acid receptors. Curr Drug Targets 2012;13:1659-64. https://doi.org/10.2174/138945012803529947
  9. Choi SH, Lee BH, Hwang SH, Kim HJ, Lee SM, Kim HC, Rhim HW, Nah SY. Molecular mechanisms of large-conductance ca (2+) -activated potassium channel activation by ginseng gintonin. Evid Based Complement Alternat Med 2013;2013:323709.
  10. Nguyen PV, Abel T, Kandel ER, Bourtchouladze R. Strain-dependent differences in LTP and hippocampus-dependent memory in inbred mice. Learn Mem 2000;7:170-9. https://doi.org/10.1101/lm.7.3.170
  11. Weeber EJ, Atkins CM, Selcher JC, Varga AW, Mirnikjoo B, Paylor R, Leitges M, Sweatt JD. A role for the beta isoform of protein kinase C in fear conditioning. J Neurosci 2000;20:5906-14. https://doi.org/10.1523/JNEUROSCI.20-16-05906.2000
  12. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248-54. https://doi.org/10.1016/0003-2697(76)90527-3
  13. Hwang SH, Shin EJ, Shin TJ, Lee BH, Choi SH, Kang J, Kim HJ, Kwon SH, Jang CG, Lee JH, et al. Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates Alzheimer's disease-related neuropathies: involvement of non-amyloidogenic processing. J Alzheimers Dis 2012;31:207-23. https://doi.org/10.3233/JAD-2012-120439
  14. Kandel ER. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 2012;5:14. https://doi.org/10.1186/1756-6606-5-14
  15. Bito H, Deisseroth K, Tsien RW. CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression. Cell 1996;87:1203-14. https://doi.org/10.1016/S0092-8674(00)81816-4
  16. Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 1989;59:675-80. https://doi.org/10.1016/0092-8674(89)90013-5
  17. Barco A, Alarcon JM, Kandel ER. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 2002;108:689-703. https://doi.org/10.1016/S0092-8674(02)00657-8
  18. Hall J, Thomas KL, Everitt BJ. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci 2000;3:533-5. https://doi.org/10.1038/75698
  19. Liu IY, Lyons WE, Mamounas LA, Thompson RF. Brain-derived neurotrophic factor plays a critical role in contextual fear conditioning. J Neurosci 2004;24:7958-63. https://doi.org/10.1523/JNEUROSCI.1948-04.2004
  20. Pedraza C, Sanchez-Lopez J, Castilla-Ortega E, Rosell-Valle C, Zambrana-Infantes E, Garcia-Fernandez M, Rodriguez de Fonseca F, Chun J, Santin LJ, Estivill-Torrus G. Fear extinction and acute stress reactivity reveal a role of LPA receptor in regulating emotional-like behaviors. Brain Struct Funct 2014;219:1659-72. https://doi.org/10.1007/s00429-013-0592-9
  21. Huang YZ, Chen RS, Rothwell JC, Wen HY. The after-effect of human theta burst stimulation is NMDA receptor dependent. Clin Neurophysiol 2007;118:1028-32. https://doi.org/10.1016/j.clinph.2007.01.021
  22. Cohen AS, Raymond CR, Abraham WC. Priming of long-term potentiation induced by activation of metabotropic glutamate receptors coupled to phospholipase C. Hippocampus 1998;8:160-70. https://doi.org/10.1002/(SICI)1098-1063(1998)8:2<160::AID-HIPO8>3.0.CO;2-P
  23. Song C, Detert JA, Sehgal M, Moyer Jr JR. Trace fear conditioning enhances synaptic and intrinsic plasticity in rat hippocampus. J Neurophysiol 2012;107:3397-408. https://doi.org/10.1152/jn.00692.2011
  24. Rex CS, Chen LY, Sharma A, Liu J, Babayan AH, Gall CM, Lynch G. Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J Cell Biol 2009;186:85-97. https://doi.org/10.1083/jcb.200901084
  25. Lu Y, Christian K, Lu B. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 2008;89:312-23. https://doi.org/10.1016/j.nlm.2007.08.018
  26. Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 1996;16:1137-45. https://doi.org/10.1016/S0896-6273(00)80140-3
  27. Gruart A, Sciarretta C, Valenzuela-Harrington M, Delgado-Garcia JM, Minichiello L. Mutation at the TrkB PLCgamma-docking site affects hippocampal LTP and associative learning in conscious mice. Learn Mem 2007;14:54-62. https://doi.org/10.1101/lm.428307
  28. Minichiello L. TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 2009;10:850-60. https://doi.org/10.1038/nrn2738
  29. Yoshii A, Constantine-Paton M. BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation. Nat Neurosci 2007;10:702-11. https://doi.org/10.1038/nn1903
  30. Mizuno M, Yamada K, Maekawa N, Saito K, Seishima M, Nabeshima T. CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning. Behav Brain Res 2002;133:135-41. https://doi.org/10.1016/S0166-4328(01)00470-3
  31. Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2001;2:599-609.
  32. Gruart A, Benito E, Delgado-Garcia JM, Barco A. Enhanced cAMP response element-binding protein activity increases neuronal excitability, hippocampal long-term potentiation, and classical eyeblink conditioning in alert behaving mice. J Neurosci 2012;32:17431-41. https://doi.org/10.1523/JNEUROSCI.4339-12.2012
  33. Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE, Crook B, Davies CH, Dawson LA, Grau E, Heidbreder C, et al. LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease. Mol Cell Neurosci 2003;24:1170-9. https://doi.org/10.1016/j.mcn.2003.09.001

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