Russian Journal of Biological Physics and Chemisrty Russian Journal of Biological Physics and Chemisrty АКТУАЛЬНЫЕ ВОПРОСЫ БИОЛОГИЧЕСКОЙ ФИЗИКИ И ХИМИИ 2499-9962 54421 Моделирование в биофизике Modelling in biophycis Моделирование в биофизике EFFECT OF MUTANT FORMS OF SYNAPTIC NMDA RECEPTORS ON OSCILLATIONS IN NEURAL NETWORKS ВЛИЯНИЕ МУТАНТНЫХ ФОРМ СИНАПТИЧЕСКИХ РЕЦЕПТОРОВ NMDA НА ОСЦИЛЛЯЦИИ В НЕЙРОННЫХ СЕТЯХ Аксенова С В Aksenova S V Батова А С Batova A S Бугай А Н Bugay A N Душанов Э Б Dushanov E B dushanov@jinr.ru Объединенный институт ядерных исследований ru Joint Institute for Nuclear Research ru Объединенный институт ядерных исследований ru Joint Institute for Nuclear Research ru Объединенный институт ядерных исследований ru Joint Institute for Nuclear Research ru Объединенный институт ядерных исследований ru Joint Institute for Nuclear Research ru 25 06 2019 25 06 2019 4 2 209 213 20 06 2019 20 06 2019 https://rusjbpc.ru/en/nauka/article/54421/view

В работе было проведено молекулярно-динамическое моделирование активации ионного канала мутантных форм NMDA-рецептора. Анализировались би и тригетеромерные формы рецептора с различной композицией субъединиц. Проводимость ионного канала вычислялась по данным пакета HOLE, а также анализа связывания ионов магния. Анализ полученных структур позволил определить изменение проводимостей ионного канала, которые сильно уменьшались в случае двойных точковых мутаций и делеций. Полученные данные использовались в модели нейронной сети гиппокампа в пакете NEURON. В результате удалось исследовать влияние мутаций, кодирующих белковые субъединицы NMDA-рецепторов, на генерацию тэта - и гамма -ритмов.

In the present work, molecular dynamics simulation of the ion channel activation of mutant forms of the NMDA receptor was carried out. The bi and triheteromeric forms of the receptor with different compositions of the subunits were analyzed. The conductivity of the ion channel was calculated according to the HOLE program, as well as by analyzing the binding of magnesium ions. The analysis of the structures obtained made it possible to determine the change in the conductivities of the ion channel, which strongly decreased in the case of double point mutations and deletions. The data obtained were used in the hippocampal neural network model in the NEURON package. As a result, it was possible to investigate the effect of mutations encoding the protein subunits of the NMDA receptors on the generation of theta and gamma rhythms.

 ЦНС гиппокамп генные мутации моделирование CNS hippocampus gene mutations modelling

Григорьев А.И., Красавин Е.А., Островский М.А. К вопросу о радиационном барьере при пилотируемых межпланетных полетах. Вестник Российской академии наук, 2017, т. 87, № 1, с. 65-69. [Grigoriev A.I., Krasavin E.A., Ostrovsky M.A. On the radiation barrier in manned interplanetary flights. Bulletin of the Russian Academy of Sciences, 2017, vol. 87, no. 1, pp. 65-69. (In Russ.)] Grigor'ev A.I., Krasavin E.A., Ostrovskiy M.A. K voprosu o radiacionnom bar'ere pri pilotiruemyh mezhplanetnyh poletah. Vestnik Rossiyskoy akademii nauk, 2017, t. 87, № 1, s. 65-69. [Grigoriev A.I., Krasavin E.A., Ostrovsky M.A. On the radiation barrier in manned interplanetary flights. Bulletin of the Russian Academy of Sciences, 2017, vol. 87, no. 1, pp. 65-69. (In Russ.)] Shi L., Adams M.M., Long A., Carter C.C., Bennett C., Sonntag W.E., Nicolle M.M., Robbins M., D’Agostino R.Jr., Brunso-Bechtold J.K. Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus. Radiat. Res., 2006, vol. 166, pp. 892-899. Shi L., Adams M.M., Long A., Carter C.C., Bennett C., Sonntag W.E., Nicolle M.M., Robbins M., D’Agostino R.Jr., Brunso-Bechtold J.K. Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus. Radiat. Res., 2006, vol. 166, pp. 892-899. Burnashev N., Szepetowski P. NMDA receptor subunit mutations in neurodevelopmental disorders. Curr. Opin. Pharmacol., 2015, vol. 20, pp. 73-82. Burnashev N., Szepetowski P. NMDA receptor subunit mutations in neurodevelopmental disorders. Curr. Opin. Pharmacol., 2015, vol. 20, pp. 73-82. Boreyko A.V., Bugay A.N., Bulanova T.S., Dushanov E.B., Jezkova L., Kulikova E.A., Smirnova E.V., Zadneprianetc M.G., Krasavin E.A. Clustered DNA double-strand breaks and neuroradiobiological effects of accelerated charged particles. Physics of Particles and Nuclei Letters, 2018, vol. 15, no. 5, pp. 551-561. Boreyko A.V., Bugay A.N., Bulanova T.S., Dushanov E.B., Jezkova L., Kulikova E.A., Smirnova E.V., Zadneprianetc M.G., Krasavin E.A. Clustered DNA double-strand breaks and neuroradiobiological effects of accelerated charged particles. Physics of Particles and Nuclei Letters, 2018, vol. 15, no. 5, pp. 551-561. Phillips J.C., Braun R., Wang W., Gumbart J., Tajkhorshid E., Villa E., Chipot C., Skeel R.D., Kale L., Schulten K. Scalable molecular dynamics with NAMD. J. Comput Chem., 2005, vol. 26, no. 16, pp. 1781-1802. Phillips J.C., Braun R., Wang W., Gumbart J., Tajkhorshid E., Villa E., Chipot C., Skeel R.D., Kale L., Schulten K. Scalable molecular dynamics with NAMD. J. Comput Chem., 2005, vol. 26, no. 16, pp. 1781-1802. Tajima N, Karakas E, Grant T, Simorowski N, Diaz-Avalos R., Grigorieff N., Furukawa H. Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature, 2016, vol. 534, no. 7605, pp. 63-68. Tajima N, Karakas E, Grant T, Simorowski N, Diaz-Avalos R., Grigorieff N., Furukawa H. Activation of NMDA receptors and the mechanism of inhibition by ifenprodil. Nature, 2016, vol. 534, no. 7605, pp. 63-68. Sali A., Blundell T. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol., 1993, vol. 234, no. 3, pp. 779-815. Sali A., Blundell T. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol., 1993, vol. 234, no. 3, pp. 779-815. Lemke J.R., Hendrickx R., Geider K., Laube B., Schwake M., Harvey R.J., James V.M., Pepler A., Steiner I., Hortnagel K., Neidhardt J., Ruf S., Wolff M., Bartholdi D., Caraballo R., Platzer K., Suls A., Jonghe P.D., Biskup S., Weckhuysen S. GRIN2B mutations in west syndrome and intellectual disability with focal epilepsy. Ann Neurol., 2014, vol. 75, no. 1, pp. 147-154. Lemke J.R., Hendrickx R., Geider K., Laube B., Schwake M., Harvey R.J., James V.M., Pepler A., Steiner I., Hortnagel K., Neidhardt J., Ruf S., Wolff M., Bartholdi D., Caraballo R., Platzer K., Suls A., Jonghe P.D., Biskup S., Weckhuysen S. GRIN2B mutations in west syndrome and intellectual disability with focal epilepsy. Ann Neurol., 2014, vol. 75, no. 1, pp. 147-154. Grubmüller H., Groll V. Solvate. Max Plank Institute for Biophysical Chemistry, 2013. URL: http://www.mpibpc.mpg.de/grubmueller/solvate Grubmüller H., Groll V. Solvate. Max Plank Institute for Biophysical Chemistry, 2013. URL: http://www.mpibpc.mpg.de/grubmueller/solvate Smart O.S., Neduvelil J.G., Wang X., Wallace B.A., Sansom M.S. HOLE: A program for the analysis of the pore dimensions of ion channel structural models. J. of Molec. Graphics, 1996, vol. 14, no. 6, pp. 354-360. Smart O.S., Neduvelil J.G., Wang X., Wallace B.A., Sansom M.S. HOLE: A program for the analysis of the pore dimensions of ion channel structural models. J. of Molec. Graphics, 1996, vol. 14, no. 6, pp. 354-360. Fedele L., Newcombe J., Topf M., Gibb A., Harvey R.J., Smart T.G., Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nat. Commun., 2018, vol. 9, p. 957. Fedele L., Newcombe J., Topf M., Gibb A., Harvey R.J., Smart T.G., Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nat. Commun., 2018, vol. 9, p. 957. Cutsuridis V., Graham B.P., Cobb S., Vida I. Hippocampal Microcircuits. A Computational Modeler’s Resource Book. Springer-Verlag New York, 2010. ISBN: 978-1-4419-0995-4. P. XI, 617. Cutsuridis V., Graham B.P., Cobb S., Vida I. Hippocampal Microcircuits. A Computational Modeler’s Resource Book. Springer-Verlag New York, 2010. ISBN: 978-1-4419-0995-4. P. XI, 617. Neymotin S.A., Lazarewicz M.T., Sherif M., Contreras D., Finkel L.H., Lytton W.W. Ketamine disrupts theta modulation of gamma in a computer model of hippocampus. J. Neurosci., 2011, vol. 31, no. 32, pp. 11733-11743. Neymotin S.A., Lazarewicz M.T., Sherif M., Contreras D., Finkel L.H., Lytton W.W. Ketamine disrupts theta modulation of gamma in a computer model of hippocampus. J. Neurosci., 2011, vol. 31, no. 32, pp. 11733-11743. Tort A.B., Rotstein H.G., Dugladze T., Gloveli T., Kopell N.J. On the formation of gamma-coherent cell assemblies by oriens lacunosum-moleculare interneurons in the hippocampus. PNAS, 2007, vol. 104, no. 33, pp. 13490-13495. Tort A.B., Rotstein H.G., Dugladze T., Gloveli T., Kopell N.J. On the formation of gamma-coherent cell assemblies by oriens lacunosum-moleculare interneurons in the hippocampus. PNAS, 2007, vol. 104, no. 33, pp. 13490-13495. Jahr C., Stevens C. Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics. J. Neurosci., 1990, vol. 10, no 9, pp. 3178-3182. Jahr C., Stevens C. Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics. J. Neurosci., 1990, vol. 10, no 9, pp. 3178-3182.