vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ16.217vavilov-878Research ArticleМоделирование патологийModeling of disordersАутизм как проявление нарушения молекулярных механизмов регуляции развития и функций синапсовMolecular mechanisms of autism as a form of synaptic dysfunctionТрифоноваЕ. А.TrifonovaE. A.

Новосибирск, Россия

Novosibirsk, Russia

trifonova.k@rambler.ruХлебодароваТ. М.KhlebodarovaT. M.

Новосибирск, Россия

Novosibirsk, Russia

ГрунтенкоН. Е.GruntenkoN. E.

Новосибирск, Россия

Novosibirsk, Russia

Федеральное государственное бюджетное научное учреждение «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук»РоссияInstitute of Cytology and Genetics SB RASRussian Federation201603022017206959967Copyright © Трифонова Е.А., Хлебодарова Т.М., Грунтенко Н.Е., 20172017Трифонова Е.А., Хлебодарова Т.М., Грунтенко Н.Е.Trifonova E.A., Khlebodarova T.M., Gruntenko N.E.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/878

Расстройства аутистического спектра – отдельная группа дефектов развития с очень высокой генетической компонентой. Генетический скрининг выявил множество различных генетических вариаций, связанных с аутизмом, а биоинформатический анализ сигнальных путей и генных сетей привел к пониманию, что многие из этих мутационных изменений вовлечены в функционирование синапсов. Синапс является местом электрохимической коммуникации между нейронами и необходимой субъединицей для обучения и формирования памяти. Межнейронная коммуникативная связь пластична, и наиболее стойкие формы синаптической пластичности сопровождаются изменениями в биосинтезе белка как в теле нейронов, так и локально в дендритах. Локальная трансляция – это тонко регулируемый процесс, центральную роль в регуляции инициации которого играет сигнальный путь mTOR (mammalian or mechanistic target of rapamycin). Мутационное повреждение хотя бы одного из звеньев этого сигнального пути приводит к нарушениям синаптической пластичности и поведения. С нарушениями регуляции локальной трансляции в дендритах связаны моногенные синдромы Нунана, Костелло, Каудена, Ретта, туберозный склероз, нейрофиброматоз I типа и синдром ломкой Х-хромосомы, у части носителей которых также диагностируются расстройства аутистического спектра. Данный обзор посвящен молекулярным механизмам синдромного аутизма, обусловленного моногенными мутациями, а также механизм обоснованной терапии некоторых расстройств аутистического спектра.

Autism spectrum disorders are a separate group of defects with a very high genetic component. Genetic screening has identified hundreds of mutations and other genetic variations associated with autism, and bioinformatic analysis of signaling pathways and gene networks has led to understanding that many of these mutational changes are involved in the functioning of synapses. A synapse is a site of electrochemical communication between neurons and an essential subunit for learning and memory. Interneuronal communicative relationships are plastic. The most prominent forms of synaptic plasticity are accompanied by changes in protein biosynthesis, both in neuron body and in dendrites. Protein biosynthesis or translation is a carefully regulated process, with a central role played by mTOR (mammalian or mechanistic target of rapamycin). Normally mTOR-regulated translation is slightly inhibited, and in most cases mutational damage to at least one of the links of the mTOR signaling pathway, increases translation and leads to impaired synaptic plasticity and behavior. Deregulation of the local translation in dendrites is connected with the following monogenic autism spectrum disorders: neurofibromatosis type 1, Noonan syndrome, Costello syndrome, Cowden syndrome, tuberous sclerosis, fragile X chromosome, syndrome, and Rett syndrome. The review considers the most important mutations leading to monogenic autism, as well as the possibility of a mechanism-based treatment of certain disorders of the autism spectrum.

расстройства аутистического спектра (РАС)синапсmTORмеханизм-обоснованная терапиясиндромный аутизм.autism spectrum disorders (ASD)the synapsemechanistic or mammalian target of rapamycin (mTOR)mechanism-based therapysyndromic autismReferencesAllingham-Hawkins D.J., Babul-Hirji R., Chitayat D., Holden J.J., Yang K.T., Lee C., … Costa S.S., Otto P.A., Mingroni-Netto R.C., Murray A., Webb J., Vieri F. Fragile X premutation is a significant risk factor for premature ovarian failure: The International Collaborative POF in Fragile X study-preliminary data. Am. J. Med. Genet. 1999;83(4):322-325. DOI 10.1002/(SICI)1096-8628(19990402)83:4<322::AID-AJMG17>3.0.CO;2-B [pii].Allingham-Hawkins D.J., Babul-Hirji R., Chitayat D., Holden J.J., Yang K.T., Lee C., … Costa S.S., Otto P.A., Mingroni-Netto R.C., Murray A., Webb J., Vieri F. Fragile X premutation is a significant risk factor for premature ovarian failure: The International Collaborative POF in Fragile X study-preliminary data. Am. J. Med. Genet. 1999;83(4):322-325. DOI 10.1002/(SICI)1096-8628(19990402)83:4<322::AID-AJMG17>3.0.CO;2-B [pii].Angelidou A., Alysandratos K.-D., Asadi S., Zhang B., Francis K., Vasiadi M., … Theoharides T.C. Brief Report: “Allergic Symptoms” in Children with Autism Spectrum Disorders. More than Meets the Eye? J. Autism Dev. Disord. 2011;41(11):1579-1585. DOI 10.1007/s10803- 010-1171-z.Angelidou A., Alysandratos K.-D., Asadi S., Zhang B., Francis K., Vasiadi M., … Theoharides T.C. Brief Report: “Allergic Symptoms” in Children with Autism Spectrum Disorders. More than Meets the Eye? J. Autism Dev. Disord. 2011;41(11):1579-1585. DOI 10.1007/s10803- 010-1171-z.Bagni C., Oostra B.A. Fragile X syndrome: from protein function to therapy. Am. J. Med. Genet. Part A. 2013;161(11):2809-2821. DOI 10.1002/ajmg.a.36241.Bagni C., Oostra B.A. Fragile X syndrome: from protein function to therapy. Am. J. Med. Genet. Part A. 2013;161(11):2809-2821. DOI 10.1002/ajmg.a.36241.Belichenko P.V., Wright E.E., Belichenko N.P., Masliah E., Li H.H., Mobley W.C., Francke U. Widespread changes in dendritic and axonal morphology in Mecp2-mutant mouse models of Rett syndrome: Evidence for disruption of neuronal networks. J. Comp. Neurol. 2009;514(3):240-258. DOI 10.1002/cne.22009.Belichenko P.V., Wright E.E., Belichenko N.P., Masliah E., Li H.H., Mobley W.C., Francke U. Widespread changes in dendritic and axonal morphology in Mecp2-mutant mouse models of Rett syndrome: Evidence for disruption of neuronal networks. J. Comp. Neurol. 2009;514(3):240-258. DOI 10.1002/cne.22009.Böckers T.M., Mameza M.G., Kreutz M.R., Bockmann J., Weise C., Buck F., … Kreienkamp H.J. Synaptic scaffolding proteins in rat brain: Ankyrin repeats of the multidomain Shank protein family interact with the cytoskeletal protein α-fodrin. J. Biol. Chem. 2001; 276(43):40104-40112. DOI 10.1074/jbc.M102454200.Böckers T.M., Mameza M.G., Kreutz M.R., Bockmann J., Weise C., Buck F., … Kreienkamp H.J. Synaptic scaffolding proteins in rat brain: Ankyrin repeats of the multidomain Shank protein family interact with the cytoskeletal protein α-fodrin. J. Biol. Chem. 2001; 276(43):40104-40112. DOI 10.1074/jbc.M102454200.Bozdagi O., Sakurai T., Papapetrou D., Wang X., Dickstein D.L., Takahashi N., … Buxbaum J.D. Haploinsufficiency of the autismassociated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol. Autism. 2010;1(1):15. DOI 2040- 2392-1-15 [pii]n10.1186/2040-2392-1-15.Bozdagi O., Sakurai T., Papapetrou D., Wang X., Dickstein D.L., Takahashi N., … Buxbaum J.D. Haploinsufficiency of the autismassociated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol. Autism. 2010;1(1):15. DOI 2040- 2392-1-15 [pii]n10.1186/2040-2392-1-15.Chang S., Bray S.M., Li Z., Zarnescu D.C., He C., Jin P., Warren S.T. Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. Nat. Chem. Biol. 2008;4(4):256-263. DOI 10.1038/nchembio.78.Chang S., Bray S.M., Li Z., Zarnescu D.C., He C., Jin P., Warren S.T. Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. Nat. Chem. Biol. 2008;4(4):256-263. DOI 10.1038/nchembio.78.Chen R.Z., Akbarian S., Tudor M., Jaenisch R. Deficiency of methyl- CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 2001;27(3):327-331. DOI 10.1038/85906.Chen R.Z., Akbarian S., Tudor M., Jaenisch R. Deficiency of methyl- CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 2001;27(3):327-331. DOI 10.1038/85906.Curatolo P., Bombardieri R., Jozwiak S. Tuberous sclerosis. Lancet. 2008;372(9639):657-668. DOI 10.1016/S0140-6736(08)61279-9.Curatolo P., Bombardieri R., Jozwiak S. Tuberous sclerosis. Lancet. 2008;372(9639):657-668. DOI 10.1016/S0140-6736(08)61279-9.Deogracias R., Yazdani M., Dekkers M.P.J., Guy J., Ionescu M.C.S., Vogt K.E., Barde Y.-A. Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc. Natl. Acad. Sci. USA. 2012;109(35):14230-14235. DOI 10.1073/pnas.1206093109.Deogracias R., Yazdani M., Dekkers M.P.J., Guy J., Ionescu M.C.S., Vogt K.E., Barde Y.-A. Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc. Natl. Acad. Sci. USA. 2012;109(35):14230-14235. DOI 10.1073/pnas.1206093109.Dolan B.M., Duron S.G., Campbell D.A., Vollrath B., Shankaranarayana Rao B.S., Ko H.-Y., … Tonegawa S. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small- molecule PAK inhibitor FRAX486. Proc. Natl. Acad. Sci. USA. 2013;110(14):5671-5676. DOI 10.1073/pnas.1219383110.Dolan B.M., Duron S.G., Campbell D.A., Vollrath B., Shankaranarayana Rao B.S., Ko H.-Y., … Tonegawa S. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small- molecule PAK inhibitor FRAX486. Proc. Natl. Acad. Sci. USA. 2013;110(14):5671-5676. DOI 10.1073/pnas.1219383110.Durand C.M., Betancur C., Boeckers T.M., Bockmann J., Chaste P., Fauchereau F., … Bourgeron T. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 2007;39(1):25-27. DOI 10.1038/ng1933.Durand C.M., Betancur C., Boeckers T.M., Bockmann J., Chaste P., Fauchereau F., … Bourgeron T. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 2007;39(1):25-27. DOI 10.1038/ng1933.Ebrahimi-Fakhari D., Sahin M. Autism and the synapse: emerging mechanisms and mechanism-based therapies. Curr. Opin. Neurol. 2015;1(617):1-12. DOI 10.1097/WCO.0000000000000186.Ebrahimi-Fakhari D., Sahin M. Autism and the synapse: emerging mechanisms and mechanism-based therapies. Curr. Opin. Neurol. 2015;1(617):1-12. DOI 10.1097/WCO.0000000000000186.Ehninger D., Han S., Shilyansky C., Zhou Y., Li W., David J. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat. Med. 2009;14(8):843-848. DOI 10.1038/nm1788.Reversal.Ehninger D., Han S., Shilyansky C., Zhou Y., Li W., David J. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat. Med. 2009;14(8):843-848. DOI 10.1038/nm1788.Reversal.Ehninger D., Silva A.J. Rapamycin for treating Tuberous sclerosis and Autism Spectrum disorders. Trends Mol. Med. 2011;17(2):78-87. DOI 10.1016/j.molmed.2010.10.002.Ehninger D., Silva A.J. Rapamycin for treating Tuberous sclerosis and Autism Spectrum disorders. Trends Mol. Med. 2011;17(2):78-87. DOI 10.1016/j.molmed.2010.10.002.El-Fishawy P., State M.W. The genetics of autism: key issues, recent findings, and clinical implications. Psychiatr. Clin. North Am. 2010; 33(1):83-105. DOI 10.1016/j.psc.2009.12.002.El-Fishawy P., State M.W. The genetics of autism: key issues, recent findings, and clinical implications. Psychiatr. Clin. North Am. 2010; 33(1):83-105. DOI 10.1016/j.psc.2009.12.002.Gadad B.S., Li W., Yazdani U., Grady S., Johnson T., Hammond J., … German D.C. Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology. Proc. Natl. Acad. Sci. USA. 2015;112(40):12498-12503. DOI 10.1073/pnas.1500968112.Gadad B.S., Li W., Yazdani U., Grady S., Johnson T., Hammond J., … German D.C. Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology. Proc. Natl. Acad. Sci. USA. 2015;112(40):12498-12503. DOI 10.1073/pnas.1500968112.Ghosh R.P., Horowitz-Scherer R.A., Nikitina T., Shlyakhtenko L.S., Woodcock C.L. MeCP2 binds cooperatively to its substrate and competes with histone H1 for chromatin binding sites. Mol. Cell. Biol. 2010;30(19):4656-4670. DOI 10.1128/MCB.00379-10.Ghosh R.P., Horowitz-Scherer R.A., Nikitina T., Shlyakhtenko L.S., Woodcock C.L. MeCP2 binds cooperatively to its substrate and competes with histone H1 for chromatin binding sites. Mol. Cell. Biol. 2010;30(19):4656-4670. DOI 10.1128/MCB.00379-10.Greer P.L., Hanayama R., Bloodgood B.L., Mardinly A.R., Lipton D.M., Flavell S.W., … Greenberg M.E. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell. 2010;140(5):704-716. DOI 10.1016/j.cell.2010.01.026.Greer P.L., Hanayama R., Bloodgood B.L., Mardinly A.R., Lipton D.M., Flavell S.W., … Greenberg M.E. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell. 2010;140(5):704-716. DOI 10.1016/j.cell.2010.01.026.Guy J., Hendrich B., Holmes M., Martin J.E., Bird A. A mouse Mecp2- null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 2001;27(3):322-326. DOI 10.1038/85899.Guy J., Hendrich B., Holmes M., Martin J.E., Bird A. A mouse Mecp2- null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 2001;27(3):322-326. DOI 10.1038/85899.Hata Y., Butz S., Südhof T.C. CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J. Neurosci. 1996;16(8):2488-2494. DOI papers2://publication/uuid/43B65FDC-BC39-4EC1- 8178-47495149E5C1.Hata Y., Butz S., Südhof T.C. CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J. Neurosci. 1996;16(8):2488-2494. DOI papers2://publication/uuid/43B65FDC-BC39-4EC1- 8178-47495149E5C1.Irie M., Hata Y., Takeuchi M., Ichtchenko K., Toyoda A., Hirao K., … Südhof T.C. Binding of neuroligins to PSD-95. Science. 1997;277: 1511-1515. DOI 10.1126/science.277.5331.1511.Irie M., Hata Y., Takeuchi M., Ichtchenko K., Toyoda A., Hirao K., … Südhof T.C. Binding of neuroligins to PSD-95. Science. 1997;277: 1511-1515. DOI 10.1126/science.277.5331.1511.Jamain S., Quach H., Betancur C., Råstam M., Colineaux C., Gillberg I.C., … Bourgeron T. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 2003;34(1):27-29. DOI 10.1038/ng1136.Jamain S., Quach H., Betancur C., Råstam M., Colineaux C., Gillberg I.C., … Bourgeron T. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 2003;34(1):27-29. DOI 10.1038/ng1136.Jamain S., Radyushkin K., Hammerschmidt K., Granon S., Boretius S., Varoqueaux F., … Brose N. Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc. Natl. Acad. Sci. USA. 2008;105(5):1710-1715. DOI 10.1073/pnas.0711555105.Jamain S., Radyushkin K., Hammerschmidt K., Granon S., Boretius S., Varoqueaux F., … Brose N. Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc. Natl. Acad. Sci. USA. 2008;105(5):1710-1715. DOI 10.1073/pnas.0711555105.Jia F., Wang B., Shan L., Xu Z., Staal W.G., Du L. Core symptoms autism improved after vitamin D supplementation. Pediatrics. 2015; 135(1):e196-e198. DOI 10.1542/peds.2014- 2121.Jia F., Wang B., Shan L., Xu Z., Staal W.G., Du L. Core symptoms autism improved after vitamin D supplementation. Pediatrics. 2015; 135(1):e196-e198. DOI 10.1542/peds.2014- 2121.Jiang Y.H., Armstrong D., Albrecht U., Atkins C.M., Noebels J.L., Eichele G., … Beaudet A.L. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron. 1998;21(4):799-811. DOI 10.1016/S0896-6273(00)80596-6.Jiang Y.H., Armstrong D., Albrecht U., Atkins C.M., Noebels J.L., Eichele G., … Beaudet A.L. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron. 1998;21(4):799-811. DOI 10.1016/S0896-6273(00)80596-6.Katz D.M. Brain-derived neurotrophic factor and rett syndrome. Handbook of Experimental Pharmacology. Eds. G.R. Lewin, B.D. Carter. Berlin: Springer-Verlag, 2014;220:481-495. DOI 10.1007/978-3-642-45106-5_18.Katz D.M. Brain-derived neurotrophic factor and rett syndrome. Handbook of Experimental Pharmacology. Eds. G.R. Lewin, B.D. Carter. Berlin: Springer-Verlag, 2014;220:481-495. DOI 10.1007/978-3-642-45106-5_18.Kelleher R.J., Bear M.F. The autistic neuron: troubled translation? Cell. 2008;135(3):401-406. DOI 10.1016/j.cell.2008.10.017.Kelleher R.J., Bear M.F. The autistic neuron: troubled translation? Cell. 2008;135(3):401-406. DOI 10.1016/j.cell.2008.10.017.Kishino T., Lalande M., Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat. Genet. 1997;15(1):70-73. DOI 10.1038/ng0197-70.Kishino T., Lalande M., Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat. Genet. 1997;15(1):70-73. DOI 10.1038/ng0197-70.Kouser M., Speed H.E., Dewey C.M., Reimers J.M., Widman A.J., Gupta N., … Powell C.M. Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission. J. Neurosci. 2013;33(47):18448-18468. DOI 10.1523/JNEUROSCI.3017-13.2013.Kouser M., Speed H.E., Dewey C.M., Reimers J.M., Widman A.J., Gupta N., … Powell C.M. Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission. J. Neurosci. 2013;33(47):18448-18468. DOI 10.1523/JNEUROSCI.3017-13.2013.Kwon C.H., Luikart B.W., Powell C.M., Zhou J., Matheny S.A., Zhang W., … Parada L.F. Pten regulates neuronal arborization social interaction in mice. Neuron. 2006;50(3):377-388. DOI 10.1016/j.neuron.2006.03.023.Kwon C.H., Luikart B.W., Powell C.M., Zhou J., Matheny S.A., Zhang W., … Parada L.F. Pten regulates neuronal arborization social interaction in mice. Neuron. 2006;50(3):377-388. DOI 10.1016/j.neuron.2006.03.023.Lipton J.O., Sahin M. The neurology of mTOR. Neuron. 2014;84(2);275-291. DOI 10.1016/j.neuron.2014.09.034.Lipton J.O., Sahin M. The neurology of mTOR. Neuron. 2014;84(2);275-291. DOI 10.1016/j.neuron.2014.09.034.Lisse T.S., Hewison M. Vitamin D: A new player in the world of mTOR signaling. Cell Cycle. 2011;10(12):1888-1889. DOI 10.4161/cc.10.12.15620.Lisse T.S., Hewison M. Vitamin D: A new player in the world of mTOR signaling. Cell Cycle. 2011;10(12):1888-1889. DOI 10.4161/cc.10.12.15620.Lisse T.S., Liu T., Irmler M., Beckers J., Chen H., Adams J.S., Hewison M. Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling. FASEB J. 2011;25(3):937-947. DOI 10.1096/fj.10-172577.Lisse T.S., Liu T., Irmler M., Beckers J., Chen H., Adams J.S., Hewison M. Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling. FASEB J. 2011;25(3):937-947. DOI 10.1096/fj.10-172577.Liu Y., Zhang D., Liu X. mTOR signaling in T cell immunity and autoimmunity. Int. Rev. Immunol. 2015;34(1):50-66. DOI 10.3109/08830185.2014.933957.Liu Y., Zhang D., Liu X. mTOR signaling in T cell immunity and autoimmunity. Int. Rev. Immunol. 2015;34(1):50-66. DOI 10.3109/08830185.2014.933957.Matsuura T., Sutcliffe J.S., Fang P., Galjaard R.J., Jiang Y.H., Benton C.S., … Beaudet A.L. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat. Genet. 1997;15:74-77. DOI 10.1038/ng0197-74.Matsuura T., Sutcliffe J.S., Fang P., Galjaard R.J., Jiang Y.H., Benton C.S., … Beaudet A.L. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat. Genet. 1997;15:74-77. DOI 10.1038/ng0197-74.Meikle L., Pollizzi K., Egnor A., Kramvis I., Lane H., Sahin M., Kwiatkowski D.J. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J. Neurosci. 2008;28(21):5422-5432. DOI 10.1523/JNEUROSCI.0955-08.2008.Meikle L., Pollizzi K., Egnor A., Kramvis I., Lane H., Sahin M., Kwiatkowski D.J. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J. Neurosci. 2008;28(21):5422-5432. DOI 10.1523/JNEUROSCI.0955-08.2008.Missler M., Südhof T.C. Neurexins: Three genes and 1001 products. Trends Genet. 1998;14(1):20-26. DOI 10.1016/S0168-9525(97)01324-3.Missler M., Südhof T.C. Neurexins: Three genes and 1001 products. Trends Genet. 1998;14(1):20-26. DOI 10.1016/S0168-9525(97)01324-3.Missler M., Zhang W., Rohlmann A., Kattenstroth G., Hammer R.E., Gottmann K., Südhof T.C. Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature. 2003;423:939- 948. DOI 10.1038/nature01755.Missler M., Zhang W., Rohlmann A., Kattenstroth G., Hammer R.E., Gottmann K., Südhof T.C. Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature. 2003;423:939- 948. DOI 10.1038/nature01755.Okamoto N., Kubota T., Nakamura Y., Murakami R., Nishikubo T., Tanaka I., … Uchino S. 22q13 microduplication in two patients with common clinical manifestations: A recognizable syndrome? Am. J. Med. Genet. Part A. 2007;143(23):2804-2809. DOI 10.1002/ajmg.a.31771.Okamoto N., Kubota T., Nakamura Y., Murakami R., Nishikubo T., Tanaka I., … Uchino S. 22q13 microduplication in two patients with common clinical manifestations: A recognizable syndrome? Am. J. Med. Genet. Part A. 2007;143(23):2804-2809. DOI 10.1002/ajmg.a.31771.Pacey L.K.K., Heximer S.P., Hampson D.R. Increased GABA(B) receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. Mol. Pharmacol. 2009;76(1):18-24.DOI 10.1124/mol.109.056127.posits.Pacey L.K.K., Heximer S.P., Hampson D.R. Increased GABA(B) receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. Mol. Pharmacol. 2009;76(1):18-24.DOI 10.1124/mol.109.056127.posits.Peça J., Feliciano C., Ting J.T., Wang W., Wells M.F., Venkatraman T.N., … Feng G. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011;472(7344):437-442. DOI 10.1038/nature09965.Peça J., Feliciano C., Ting J.T., Wang W., Wells M.F., Venkatraman T.N., … Feng G. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011;472(7344):437-442. DOI 10.1038/nature09965.Pei J.J., Hugon J. mTOR-dependent signalling in Alzheimer’s disease. J. Cell. Mol. Med. 2008;12(6B):2525-2532. DOI 10.1111/j.1582-4934.2008.00509.x.Pei J.J., Hugon J. mTOR-dependent signalling in Alzheimer’s disease. J. Cell. Mol. Med. 2008;12(6B):2525-2532. DOI 10.1111/j.1582-4934.2008.00509.x.Phelan M.C., Rogers R.C., Saul R.A., Stapleton G.A., Sweet K., Mc-Dermid H., … Kelly D.P. 22Q13 deletion syndrome. Am. J. Med. Genet. 2001;101(2):91-99. DOI 10.1002/1096- 8628(20010615)101:2<91::AID-AJMG1340>3.0.CO;2-C.Phelan M.C., Rogers R.C., Saul R.A., Stapleton G.A., Sweet K., Mc-Dermid H., … Kelly D.P. 22Q13 deletion syndrome. Am. J. Med. Genet. 2001;101(2):91-99. DOI 10.1002/1096- 8628(20010615)101:2<91::AID-AJMG1340>3.0.CO;2-C.Ricciardi S., Boggio E.M., Grosso S., Lonetti G., Forlani G., Stefanelli G., … Broccoli V. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum. Mol. Genet. 2011;20(6):1182-1196. DOI 10.1093/hmg/ddq563.Ricciardi S., Boggio E.M., Grosso S., Lonetti G., Forlani G., Stefanelli G., … Broccoli V. Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum. Mol. Genet. 2011;20(6):1182-1196. DOI 10.1093/hmg/ddq563.Riday T.T., Dankoski E.C., Krouse M.C., Fish E.W., Walsh P.L., Han J.E., … Malanga C.J. Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome. J. Clin. Invest. 2012; 122(12):4544-4554. DOI 10.1172/JCI61888.Riday T.T., Dankoski E.C., Krouse M.C., Fish E.W., Walsh P.L., Han J.E., … Malanga C.J. Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome. J. Clin. Invest. 2012; 122(12):4544-4554. DOI 10.1172/JCI61888.Roussignol G., Ango F., Romorini S., Tu J.C., Sala C., Worley P.F., …Fagni L. Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J. Neurosci. 2005;25(14):3560-3570. DOI 10.1523/JNEUROSCI.4354-04.2005.Roussignol G., Ango F., Romorini S., Tu J.C., Sala C., Worley P.F., …Fagni L. Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J. Neurosci. 2005;25(14):3560-3570. DOI 10.1523/JNEUROSCI.4354-04.2005.Sato A. mTOR, a potential target to treat autism spectrum disorder. CNS Neurol. Disord. Drug Targets. 2016;15(5):533-543. DOI 10.2174/1871527315666160413120638.Sato A. mTOR, a potential target to treat autism spectrum disorder. CNS Neurol. Disord. Drug Targets. 2016;15(5):533-543. DOI 10.2174/1871527315666160413120638.Segal R.A., Greenberg M.E. Intracellular signaling pathways activated by neurotrophic factors. Annu. Rev. Neurosci. 1996;19:463-489. DOI 10.1146/annurev.ne.19.030196.002335.Segal R.A., Greenberg M.E. Intracellular signaling pathways activated by neurotrophic factors. Annu. Rev. Neurosci. 1996;19:463-489. DOI 10.1146/annurev.ne.19.030196.002335.Shcheglovitov A., Shcheglovitova O., Yazawa M., Portmann T., Shu R., Sebastiano V., … Dolmetsch R.E. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature. 2013;503(7475):267-271. DOI 10.1038/nature12618.Shcheglovitov A., Shcheglovitova O., Yazawa M., Portmann T., Shu R., Sebastiano V., … Dolmetsch R.E. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature. 2013;503(7475):267-271. DOI 10.1038/nature12618.Sheng M., Kim E. The Shank family of scaffold proteins. J. Cell Sci. 2000;113(1):1851-1856.Sheng M., Kim E. The Shank family of scaffold proteins. J. Cell Sci. 2000;113(1):1851-1856.Singh S.K., Eroglu C. Neuroligins provide molecular links between syndromic and nonsyndromic autism. Sci. Signal. 2013;6(283):re4.DOI 10.1126/scisignal.2004102.Singh S.K., Eroglu C. Neuroligins provide molecular links between syndromic and nonsyndromic autism. Sci. Signal. 2013;6(283):re4.DOI 10.1126/scisignal.2004102.Südhof T.C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455(7215):903-911. DOI 10.1038/nature 07456.Südhof T.C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455(7215):903-911. DOI 10.1038/nature 07456.Tabuchi K., Blundell J., Etherton M.R., Hammer R.E., Liu X., Powell C.M., Südhof T.C. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007; 318(5847):71-76. DOI 10.1126/science.1146221.Tabuchi K., Blundell J., Etherton M.R., Hammer R.E., Liu X., Powell C.M., Südhof T.C. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science. 2007; 318(5847):71-76. DOI 10.1126/science.1146221.Troca-Marin J.A., Alves-Sampaio A., Montesinos M.L. Deregulated mTOR-mediated translation in intellectual disability. Prog. Neurobiol. 2012;96(2):268-282. DOI 10.1016/j.pneurobio.2012.01.005.Troca-Marin J.A., Alves-Sampaio A., Montesinos M.L. Deregulated mTOR-mediated translation in intellectual disability. Prog. Neurobiol. 2012;96(2):268-282. DOI 10.1016/j.pneurobio.2012.01.005.Tsai P., Sahin M. Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex. Curr. Opin. Neurol. 2011;24(2):106-113. DOI 10.1097/WCO.0b013e32834451c4.Tsai P., Sahin M. Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex. Curr. Opin. Neurol. 2011;24(2):106-113. DOI 10.1097/WCO.0b013e32834451c4.Varoqueaux F., Aramuni G., Rawson R.L., Mohrmann R., Missler M., Gottmann K., … Brose N. Neuroligins determine synapse maturation and function. Neuron. 2006;51(6):741-754. DOI 10.1016/j.neuron.2006.09.003.Varoqueaux F., Aramuni G., Rawson R.L., Mohrmann R., Missler M., Gottmann K., … Brose N. Neuroligins determine synapse maturation and function. Neuron. 2006;51(6):741-754. DOI 10.1016/j.neuron.2006.09.003.Veenstra-VanderWeele J., Blakely R.D. Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology. 2012;37(1):196-212. DOI 10.1038/npp.2011.185.Veenstra-VanderWeele J., Blakely R.D. Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology. 2012;37(1):196-212. DOI 10.1038/npp.2011.185.Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia. 2010;51(1):27- 36. DOI 10.1111/j.1528-1167.2009.02341.x.Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia. 2010;51(1):27- 36. DOI 10.1111/j.1528-1167.2009.02341.x.Wu J., De Theije C.M.G., Da Silva S.L., Van Der Horst H., Reinders M.T.M., Broersen L.M., … Kraneveld A.D. mTOR plays an important role in cow’s milk allergy-associated behavioral and immunological deficits. Neuropharmacology. 2015;97:220-232. DOI 10.1016/j.neuropharm.2015.04.035.Wu J., De Theije C.M.G., Da Silva S.L., Van Der Horst H., Reinders M.T.M., Broersen L.M., … Kraneveld A.D. mTOR plays an important role in cow’s milk allergy-associated behavioral and immunological deficits. Neuropharmacology. 2015;97:220-232. DOI 10.1016/j.neuropharm.2015.04.035.Xiong Q., Oviedo H.V., Trotman L.C., Zador A.M. PTEN regulation of local and long-range connections in mouse auditory cortex. J. Neurosci. 2012;32(5):1643-1652. DOI 10.1523/JNEUROSCI.4480-11.2012.Xiong Q., Oviedo H.V., Trotman L.C., Zador A.M. PTEN regulation of local and long-range connections in mouse auditory cortex. J. Neurosci. 2012;32(5):1643-1652. DOI 10.1523/JNEUROSCI.4480-11.2012.Yoo H. Genetics of autism spectrum disorder: current status and possible clinical applications. Exp. Neurobiol. 2015:24(4):257-272. DOI 10.5607/en.2015.24.4.257.Yoo H. Genetics of autism spectrum disorder: current status and possible clinical applications. Exp. Neurobiol. 2015:24(4):257-272. DOI 10.5607/en.2015.24.4.257.Zhou J., Parada L.F. PTEN signaling in autism spectrum disorders. Curr. Opin. Neurobiol. 2012;22(5):873-879. DOI 10.1016/j.conb.2012.05.004.Zhou J., Parada L.F. PTEN signaling in autism spectrum disorders. Curr. Opin. Neurobiol. 2012;22(5):873-879. DOI 10.1016/j.conb.2012.05.004.Ziemssen T., Kümpfel T., Klinkert W.E.F., Neuhaus O., Hohlfeld R. Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain. 2002;125(11):2381-2391. DOI 10.1093/brain/awf252.Ziemssen T., Kümpfel T., Klinkert W.E.F., Neuhaus O., Hohlfeld R. Glatiramer acetate-specific T-helper 1- and 2-type cell lines produce BDNF: implications for multiple sclerosis therapy. Brain-derived neurotrophic factor. Brain. 2002;125(11):2381-2391. DOI 10.1093/brain/awf252.Zoghbi H.Y., Bear M.F. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 2012;4(3):a009886. DOI 10.1101/cshperspect.a009886.Zoghbi H.Y., Bear M.F. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 2012;4(3):a009886. DOI 10.1101/cshperspect.a009886.Zweier C., de Jong E.K., Zweier M., Orrico A., Ousager L.B., Collins A.L., … Rauch A. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 2009;85(5):655-666. DOI 10.1016/j.ajhg.2009.10.004.Zweier C., de Jong E.K., Zweier M., Orrico A., Ousager L.B., Collins A.L., … Rauch A. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 2009;85(5):655-666. DOI 10.1016/j.ajhg.2009.10.004.

The authors declare that there are no conflicts of interest present.