ROLE OF THE MODULATORY MEDIATOR SEROTONIN IN THE INDUCTION OF EPIGENETIC PROCESSES DURING LONG TERM MEMORY FORMATION IN HELIX

Epigenetic mechanisms controlling long-term memory formation are a promising field in neurobiology. They include posttraslational histone modifications, which lead to chromatin remodeling and thereby influences gene expression involved in learning. Mollusks are a popular model in neurobiology, because they have relatively simple CNSs with giant neurons. Previously, we found strong induction of histone H3 acetylation and methylation during food aversion conditioning in Helix. We think that these processes are regulated by modulatory mediator serotonin, playing an important role in avoidance behavior. To study the influence of serotonin on induction of epigenetic processes, we investigated the action of an unselective antagonist of serotonin receptors, metitepine, on the acetylation and methylation of histone H3 during Helix learning. We found that metitepine treatment prevented activation of methylation and acetylation of H3 induced by learning in the CNS of the snail and deteriorates long term memory formation. Long-term memory formation in metitepine-treated animals can be improved by treatment with histone deacetylase inhibitor Na В. Our data confirm the important role of serotonin in the induction of epigenetic processes during aversion conditioning in Helix.

1. Абрамова М.С., Нистратова В.Л., Москвитин А.А., Пивоваров А.С. Метиотепин-чувствительные серотониновые рецепторы вовлечены в постсинаптический механизм сенситизации оборонительной реакции виноградной улитки // Журн. высш. нерв. деятельности. 2005. Т. 55. № 3. С. 385–392.

2. Балабан П.М., Захаров И.С. Обучение и развитие: общая основа двух явлений. М.: Наука, 1992. 152 с.

3. Гринкевич Л.Н. Эпигенетика и формирование долговременной памяти // Рос. физиол. журн. им. И.М. Сеченова. 2012а. Т. 98. № 5. С. 553–574.

4. Гринкевич Л.Н. Исследование метилирования гистона Н3 при формировании долговременной памяти // Рос. физиол. журн. им. И.М. Сеченова. 2012б. Т. 98. № 9. С. 1111–1118.

5. Гринкевич Л.Н., Лисачев П.Д., Баранова К.А., Харченко О.А. Сравнительный анализ активации МАР/ERK киназ в ЦНС животных, обладающих разной способностью к обучению // Рос. физиол. журн. им. И.М. Сеченова. 2006. Т. 92. № 5. С. 536–545.

6. Солнцева С.В., Никитин В.П. Нейрохимические механизмы консолидации ассоциативного аверсивного обучения на пищу у виноградной улитки // Рос. физиол. журн. им. И.М. Сеченова. 2008. Т. 94. № 11. С. 1259–1269.

7. Шишкина Т.Г., Дыгало Н.Н. Нейробиологические основы депрессивных расстройств и действия антидепрессантов // Журн. высш. нерв. деятельности. 2010. Т. 60. № 2. С. 138–152.

8. Abel T., Zukin R.S. Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders // Curr. Opin. Pharmacol. 2008. V. 8. No. 1. P. 57–64.

9. Akbarian S., Huang H.S. Epigenetic regulation in human brainfocus on histone lysine methylation // Biol. Psychiatry. 2009. V. 65. No. 3. P. 198–203.

10. Alarcon J.M., Malleret G., Touzani K. et al. Chromatin acetylation, memory, and LTP are impaired in CBP +/- mice: a model for the cognitive defi cit in Rubistein-Taybi syndrome and its amelioration // Neuron. 2004. V. 42. No. 6. P. 947–959.

11. Alberini C.M. Transcription factors in long-term memory and synaptic plasticity // Physiol. Rev. 2009. V. 89. No. 1. P. 121–145.

12. Barbas D., DesGroseillers L., Castellucci V.F. et al. Multiple serotonergic mechanisms contributing to sensitization in aplysia: evidence of diverse serotonin receptor subtypes // Learn Mem. 2003. V. 10. P. 373–386.

13. Berger S.L. The complex language of chromatin regulation during transcription // Nature. 2007. V. 447. P. 407–412.

14. Bredy T.W., Wu H., Crego C. et al. Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear // Learn Mem. 2007. V. 14. No. 4. Р. 268–276.

15. Danilova A.B., Grinkevich L.N. Inability of juvenile snails for long-term memory formation depends on acetylation status of histone H3 and can be improved by NaB treatment // PLoS ONE. 2012. V. 7. Issue 7. e41828. Р. 1–8.

16. Danilova A.B., Kharchenko O.A., Shevchenko K.G., Grinkevich L.N. Histone H3 acetylation is asymmetrically

17. induced upon learning in identifi ed neurons of the food aversion network in the mollusk Helix lucorum // Front. Behav. Neurosci. 2010. V. 4. No. 180. Р. 1–7.

18. Fischer A., Sananbenesi F., Wang X. et al. Recovery of learning and memory is associated with chromatin remodeling// Nature. 2007. V. 447. No. 7141. P. 178–182.

19. Gill R.K., Kumar A., Malhotra P. et al. Regulation of intestinal serotonin transporter expression via epigenetic mechanisms: role of HDAC2 // Am. J. Physiol. Cell Physiol. 2013. V. 304. No. 4. P. 334–341.

20. Grinkevich L.N., Vasil’ev G.V. Possible mechanisms of the regulation of genes expression during learning // Neurosci. Behav. Physiol. 2000. V. 30. No. 3. P. 277–292.

21. Grinkevich L.N., Lisachev P.D., Kharchenko O.A., Vasil’ev G.V. Expression of MAP/ERK kinase cascade corresponds to the ability to develop food aversion in terrestrial snail at different stages of ontogenesis // Brain Res. 2008. V. 1187. Р. 12–19.

22. Guan Z., Giustetto M., Lomvardas S. et al. Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure // Cell. 2002. V. 111. No. 4. Р. 483–493.

23. Guan J.S., Haggarty S.J., Giacometti E. et al. HDAC2 negatively regulates memory formation and synaptic plasticity // Nature. 2009. V. 459. No. 7243. Р. 55–60.

24. Gupta S., Kim S.Y., Artis S. et al. Histone methylation regulates memory formation // J. Neurosci. 2010. V. 30. No. 10. Р. 3589–3599.

25. Hart A.K., Fioravante D., Liu R.Y. et al. Serotonin-mediated synapsin expression is necessary for long-term facilitation of the Aplysia sensorimotor synapse // J. Neurosci. 2011. V. 31. No. 50. Р. 18401–18411.

26. Kandel E. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB // Mol. Brain. 2012. V. 5. No. 14. P. 1–12.

27. Kandel E.R. The molecular biology of memory storage: a dialogue between genes and synapses // Science. 2001. V. 294. No. 5544. Р. 1030–1048.

28. Kharchenko O.A., Grinkevich V.V., Vorobiova O.V., Grinkevich L.N. Learning-induced lateralized activation of the MAPK/ERK cascade in identifi ed neurons of the foodaversion network in the mollusk Helix lucorum // Neurobiol. Learn. Mem. 2010. V. 94. No. 2. Р. 158–166.

29. Korzus E., Rosenfeld M.G., Mayford M. CBP histone acetyltransferase activity is a critical component of memory consolidation // Neuron. 2004. V. 42. No. 6. P. 961–972.

30. Kuhn M., Popovic A., Pezawas L. Neuroplasticity and memory formation in major depressive disorder: An imaging genetics perspective on serotonin and BDNF // Restor Neurol. Neurosci. 2013. [Epub ahead of print].

31. Kurita M., Holloway T., García-Bea A. et al. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity // Nat. Neurosci. 2012. V. 15. No. 9. Р. 1245–1254.

32. Kurita M., Moreno J.L., Holloway T. et al. Repressive epigenetic changes at the mGlu2 promoter in frontal cortex of 5-HT2A knockout mice // Mol. Pharmacol. 2013. V. 83. No. 6. Р. 1166–1175.

33. Levenson J.M., O’Riordan K.J., Brown K.D. et al. Regulation of histone acetylation during memory formation in the hippocampus // J. Biol. Chem. 2004. V. 279. Р. 40545–40559.

34. Levenson J.M., Sweatt J.D. Epigenetic mechanisms: a common theme in vertebrate and invertebrate memory formation // Cell Mol. Life Sci. 2006. V. 63. Р. 1009–1016.

35. Ressler K.J., Paschall G., Zhou X.L., Davis M. Regulation of synaptic plasticity genes during consolidation of fear conditioning // J Neurosci. 2002. V. 22. No. 18. Р. 7892–7902.

36. Stadler F., Kolb G., Rubusch L. et al. Histone methylation at gene promoters is associated with developmental regulation and region-specifi c expression of ionotropic and metabotropic glutamate receptors in human brain // J. Neurochem. 2005. V. 94. No. 2. Р. 324–336.

37. Strahl B.D., Allis C.D. The language of covalent histone modifications // Nature. 2000. V. 403. No. 6765. Р. 41–45.

38. Takase K., Oda S., Kuroda M., Funato H. Monoaminergic and neuropeptidergic neurons have distinct expression profi les of histone deacetylases // PLoS One. 2013. V. 8. No. 3. e58473 Р. 1–19.

39. Wood M.A., Hawk J.D., Abel T. Combinatorial chromatin modifi cations and memory storage: A code for memory // Learn. Mem. 2006. V. 13. Р. 241–244.

40. Yamawaki Y., Fuchikami M., Morinobu S. et al. Antidepressant-like effect of sodium butyrate (HDAC inhibitor) and its molecular mechanism of action in the rat hippocampus // World J. Biol. Psychiatry. 2012. V. 13. No. 6. Р. 458–467.

41. Zhao J., Goldberg J., Bremner J.D., Vaccadrino V. Association between promoter methylation of serotonin transporter gene and depressive symptoms: a monozygotic twin study // Psychosom. Med. 2013. V. 75. No. 6. Р. 523–529.