I.P. Pavlov Journal of Higher Nervous ActivityI.P. Pavlov Journal of Higher Nervous ActivityЖурнал высшей нервной деятельности им. И.П. Павлова0044-46773034-5316The Russian Academy of Sciences69642710.31857/S0044467725060081ФИЗИОЛОГИЧЕСКИЕ МЕХАНИЗМЫ ПОВЕДЕНИЯ ЖИВОТНЫХ: ВОСПРИЯТИЕ ВНЕШНИХ СТИМУЛОВ, ДВИГАТЕЛЬНАЯ АКТИВНОСТЬ, ОБУЧЕНИЕ И ПАМЯТЬФИЗИОЛОГИЧЕСКИЕ МЕХАНИЗМЫ ПОВЕДЕНИЯ ЖИВОТНЫХ: ВОСПРИЯТИЕ ВНЕШНИХ СТИМУЛОВ, ДВИГАТЕЛЬНАЯ АКТИВНОСТЬ, ОБУЧЕНИЕ И ПАМЯТЬResearch ArticleThe contribution of transglutaminase-mediated processes to the maintenance and reconsolidation of the long-term context memory in snailsВклад трансглутаминаза-опосредованных процессов в поддержание и реконсолидацию долговременной обстановочной памяти виноградной улиткиZuzinaA. B.ЗюзинаА. Б.lucky-a89@mail.ruVinarskayaA. K.ВинарскаяА. Х.lucky-a89@mail.ruBalabanP. M.БалабанП. М.lucky-a89@mail.ruInstitute of Higher Nervous Activity and Neurophysiology, RASФедеральное государственное бюджетное учреждение науки Институт высшей нервной деятельности и нейрофизиологии РАН15112025756VOL 75, NO6 (2025)ТОМ 75, №6 (2025)77077718112025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://innoscience.ru/0044-4677/article/view/696427

The effects of the transglutaminase inhibitor monodansylcadaverine on context memory maintenance and reconsolidation practically are not investigated. This work was devoted to the analysis of the role of transglutaminase (TG) in the formation, maintenance, and reconsolidation of long-term context memory in the terrestrial snail Helix lucorum. We used the transglutaminase inhibitor monodansylcadaverine and demonstrated an irreversible loss of memory if the inhibitor was injected 24 hrs after training. In conditions of memory reactivation effects of TG inhibitor were absent or diminished suggesting a role of TG in memory maintenance. Obtained results can be explained by participation of TG in epigenetic regulation. Exact mechanisms should be investigated in future.

Эффекты трансглутаминазы (ТГ) реализуются через модификацию белков цитоскелета и малых G-белков, эпигенетические изменения и влияние на нейрогенез, что делает ее универсальным регулятором пластичности. Тем не менее, несмотря на широкое распространение ТГ у беспозвоночных, у наземных улиток ее присутствие и функции остаются практически неизученными. Цель настоящей работы состояла в изучении влияния активности ТГ на поддержание и реконсолидацию долговременной обстановочной памяти у виноградной улитки Helix lucorum. В настоящем исследовании мы применяли ингибитор ТГ монодансилкадаверин и показали, что ТГ является критическим компонентом поддержания долговременной обстановочной памяти у Helix lucorum. Ингибирование ТГ без реактивации вызывало необратимую утрату памяти, тогда как ее блокада совместно с напоминанием не нарушала память, что подчеркивает ключевую роль ТГ в фазе поддержания, но не реконсолидации памяти. Полученные результаты могут быть объяснены способностью ТГ выступать как регулятор генной экспрессии, однако конкретные гены-мишени и механизмы транскрипционной регуляции еще предстоит выявить.

transglutaminasemonodansylcadaverinelong-term memorymolluskтрансглутаминазамонодансилкадавериндолговременная памятьмоллюскиРабота поддержана грантом РНФ № 24-15-00149.Al-Kachak A., Maze I. Post-translational modifications of histone proteins by monoamine neurotransmitters. Curr. Opin. Chem. Biol. 2023. 74: 102302.Ambron R.T., Kremzner L.T. Post-translational modification of neuronal proteins: evidence for transglutaminase activity in R2, the giant cholinergic neuron of Aplysia. Proc. Natl. Acad. Sci. U S A. 1982. 79 (11): 3442–3446.Bader M. Serotonylation: serotonin signaling and epigenetics. Front. Mol. Neurosci. 2019. 12: 288.Balaban P.M., Vinarskaya A.K., Zuzina A.B., Ierusalimsky V.N., Malyshev A.Y. Impairment of the serotonergic neurons underlying reinforcement elicits extinction of the repeatedly reactivated context memory. Sci. Rep. 2016. 6: 36933.Balaban P., Bravarenko N. Long-term sensitization and environmental conditioning in terrestrial snails. Exp. Brain Research. 1993. 96 (3): 487–493.Delgado T., Emerson J., Hong M., Keillor J.W., Johnson G.V.W. Pharmacological inhibition of astrocytic transglutaminase 2 facilitates the expression of a neurosupportive astrocyte reactive phenotype in association with increased histone acetylation. Biomolecules. 2024. 14 (12): 1594.Dolge L., Aufenvenne K., Traupe H., Baumgartner W. Beta-actin is a target for transglutaminase activity at synaptic endings in chicken telencephalic cell cultures. J. Mol. Neurosci. 2012. 46 (2): 410–419.Elahi A., Emerson J., Rudlong J., Keillor J.W., Salois G., Visca A. et al. Deletion or inhibition of astrocytic transglutaminase 2 promotes functional recovery after spinal cord injury. Cells. 2021. 10: 2942.Facchiano F., Deloye F., Doussau F., Innamorati G., Ashton A.C., Dolly J.O. et al. Transglutaminase participates in the blockade of neurotransmitter release by tetanus toxin: evidence for a novel biological function. Amino Acids. 2010. 39 (1): 257–269.Fagutao F.F., Maningas M.B., Kondo H., Aoki T., Hirono I. Transglutaminase regulates immune-related genes in shrimp. Fish Shellfish Immunol. 2012. 32 (5): 711–715.Farrelly L.A., Thompson R.E., Zhao S., Lepack A.E., Lyu Y., Bhanu N.V. et al. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me. Nature. 2019. 567 (7749): 535–539.Fesus L., Piacentini M. Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem. Sci. 2002. 27 (10): 534–539.Fulton S., Mitra S., Lepack A.E., Martin J.A., Stewart A.F., Converse J. et al. Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced transcriptional and behavioral plasticity in male rats. Neuropsychopharmacology. 2022. 47 (10): 1776–1783.Ivashkin E., Melnikova V., Kurtova A., Brun N.R., Obukhova A., Khabarova M.Y. Transglutaminase activity determines nuclear localization of serotonin immunoreactivity in the early embryos of invertebrates and vertebrates. ACS Chem. Neurosci. 2019. 10 (8): 3888–3899.Jiang S.H., Wang Y.H., Hu L.P., Wang X., Li J., Zhang X.L., Zhang ZG. The physiology, pathology and potential therapeutic application of seorotonylation. J. Cell. Sci. 2021. 134 (11): jcs257337.Junkunlo K., Söderhäll K., Söderhäll I. Transglutaminase inhibition stimulates hematopoiesis and reduces aggressive behavior of crayfish, Pacifastacus leniusculus. J. Biol. Chem. 2019. 294 (2): 708–715.Junkunlo K., Söderhäll K., Söderhäll I. Transglutaminase 1 and 2 are localized in different blood cells in the freshwater crayfish Pacifastacus leniusculus. Fish Shellfish Immunol. 2020. 104: 83–91.Kandel E.R., Schwartz J.H. Molecular biology of an elementary form of learning: modulation of transmitter release. Science. 1982. 218 (4571): 433–443.Kim G.E., Park H.H. Structures of human translglutaminase 2: finding clues for interference in cross-linking mediated activity. Int. J. Mol. Sci. 2020. 21 (6): 2225.Kim H.J., Lee J.H., Cho S.Y., Jeon J.H., Kim I.G. Transglutaminase 2 mediates transcriptional regulation through BAF250a polyamination. Genes Genomics. 2021. 43 (4): 333–342.Lepack A., Werner C., Stewart A.F., Fulton S.L., Zhong P., Farrelly L.A. et al. Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking. Science. 2020. 368 (6487): 197–201.Li H., Wu J., Zhang N., Zheng Q. Transglutaminase 2-mediated histone monoaminylation and its role in cancer. Biosci. Rep. 2024. 44 (8): BSR20240493.Liu C., Gao X., Shi R.X., Wang Y.Y., He X.C., Du H.Z. et al. Microglial transglutaminase 2 deficiency causes impaired synaptic remodelling and cognitive deficits in mice. Cell Prolif. 2023. 56 (9): e13439.Lorand L., Graham R.M. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat. Rev. Mol. Cell. Biol. 2003. 4 (2): 140–156.Mi Z., Si T., Kapadia K., Li Q., Muma N.A. Receptor-stimulated transamidation induces activation of Rac1 and Cdc42 and the regulation of dendritic spines. Neuropharmacology. 2017. 117: 93–105.Peedicayil J., Santhosh S. Histone monoaminylation is a novel epigenetic mechanism in psychiatric disorders. Front. Mol. Neurosci. 2025. 18: 1534569.Shi R.X., Liu C., Xu Y.J., Wang Y.Y., He B.D., He X.C. et al. The role and mechanism of transglutaminase 2 in regulating hippocampal neurogenesis after traumatic brain injury. Cells. 2023. 12 (4): 558.Shibata T., Kawabata S.I. Pluripotency and a secretion mechanism of Drosophila transglutaminase. J. Biochem. 2018. 163 (3): 165–176.Singer M.A., Hortsch M., Goodman C.S., Bentley D. Annulin, a protein expressed at limb segment boundaries in the grasshopper embryo, is homologous to protein cross-linking transglutaminases. Dev. Biol. 1992. 154 (1): 143–159.Sirikharin R., Utairungsee T., Srisala J., Roytrakul S., Thitamadee S., Sritunyalucksana K. Cell surface transglutaminase required for nodavirus entry into freshwater prawn hemocytes. Fish Shellfish Immunol. 2019. 89: 108–116.Song Y., Kirkpatrick L.L., Schilling A.B., Helseth D.L., Chabot N., Keillor J.W. et al. Transglutaminase and polyamination of tubulin: posttranslational modification for stabilizing axonal microtubules. Neuron. 2013. 78 (1): 109–123.Stewart A.F., Lepack A.L., Fulton S.L., Safovich P., Maze I. Histone H3 dopaminylation in nucleus accumbens, but not medial prefrontal cortex, contributes to cocaine-seeking following prolonged abstinence. Mol. Cell. Neurosci. 2023. 125: 103824.Stewart A.F., Fulton S.L., Durand-de Cuttoli R., Thompson R.E., Chen P.J., Brindley E. et al. Hippocampal γCaMKII dopaminylation promotes synaptic-to-nuclear signaling and memory formation. bioRxiv [Preprint]. 2024. 2024.09.19.613951.Sugino H., Terakawa Y., Yamasaki A., Nakamura K., Higuchi Y., Matsubara J. et al. Molecular characterization of a novel nuclear transglutaminase that is expressed during starfish embryogenesis. Eur. J. Biochem. 2002. 269 (7): 1957–1967.Zaltron E., Vianello F., Ruzza A., Palazzo A., Brillo V., Celotti I. et al. The role of transglutaminase 2 in cancer: an update. Int. J. Mol. Sci. 2024. 25 (5): 2797.Zheng Q., Weekley B.H., Vinson D.A., Zhao S., Bastle R.M., Thompson R.E. et al. Bidirectional histone monoaminylation dynamics regulate neural rhythmicity. Nature. 2025. 637 (8047): 974–982.Zhu J., Shao Y., Chen K., Zhang W., Li C. A transglutaminase 2-like gene from sea cucumber Apostichopus japonicus mediates coelomocytes autophagy. Fish Shellfish Immunol. 2021. 119: 602–612.Zuzina A.B., Balaban P.M. Contribution of transglutaminase to the induction and maintenance of long-term synaptic potentiation in neurons in the common snail. Neurosci. Behav. Physiol. 2023. 53: 590–596.