Abstract
Autism spectrum disorders (ASDs) are a separate group of developmental disorders with a very large 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 the 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 is a required subunit for learning and memory. Interneuronal communicative connections are plastic. The most prominent forms of synaptic plasticity are accompanied by changes in protein biosynthesis, both in the neuron body and in dendrites. Protein biosynthesis, or translation, is a finely regulated process, with the central role played by mTOR kinase (mammalian or mechanistic target of rapamycin). A mutational aberration in at least one of the links of the mTOR signaling pathway impairs the synaptic plasticity and behavior. The deregulation of local translation in dendrites is connected with the following monogenic ASDs: neurofibromatosis type 1, Noonan syndrome, Costello syndrome, Cowden syndrome, tuberous sclerosis, fragile X syndrome, and Rett syndrome (RS). The review considers the most important mutations leading to monogenic autism. The possibility of a mechanism-based treatment of certain ASDs is discussed.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Allingham-Hawkins, D.J., Babul-Hirji, R., Chitayat, D., Holden, J.J., Yang, K.T., Lee, C., et al., 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, vol. 83, no. 4, pp. 322–325. [pii] doi 10.1002/(SICI)1096-8628(19990402)83:4<322::AIDAJMG17>3.0.CO;2-B
Angelidou, A., Alysandratos, K.-D., Asadi, S., Zhang, B., Francis, K., Vasiadi, M., et al., Brief Report: “Allergic symptoms” in children with autism spectrum disorders. More than meets the eye?, J. Autism Dev. Disord., 2011, vol. 41, no. 11, pp. 1579–1585. doi 10.1007/s10803-010-1171-z
Böckers, T.M., Mameza, M.G., Kreutz, M.R., Bockmann, J., Weise, C., Buck, F., et al., 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, vol. 276, no. 43, pp. 40104–40112. doi 10.1074/jbc.M102454200
Bagni, C. and Oostra, B.A., Fragile X syndrome: From protein function to therapy, Am. J. Med. Genet., 2013, vol. 161, no. 11, pp. 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., and 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, vol. 514, no. 3, pp. 240–258. doi 10.1002/cne.22009
Bozdagi, O., Sakurai, T., Papapetrou, D., Wang, X., Dickstein, D.L., et al., Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication, Mol. Autism, 2010, vol. 1, no. 1, pp. 15. 2040-2392-1-15[pii]\n doi 10.1186/2040-2392-1-15
Chang, S., Bray, S.M., Li, Z., Zarnescu, D.C., He, C., Jin, P., and Warren, S.T., Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila, Nat. Chem. Biol., 2008, vol. 4, no. 4, pp. 256–263. doi 10.1038/nchembio.78
Chen, R.Z., Akbarian, S., Tudor, M., and Jaenisch, R., Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice, Nat. Genet., 2001, vol. 27, no. 3, pp. 327–331. doi 10.1038/85906
Curatolo, P., Bombardieri, R., and Jozwiak, S., Tuberous sclerosis, Lancet, 2008, vol. 372, no. 9639, pp. 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., and 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. U.S.A., 2012, vol. 109, no. 35, pp. 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., et al., Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486, Proc. Natl. Acad. Sci. U.S.A., 2013, vol. 110, no. 14, pp. 5671–5676. doi 10.1073/pnas.1219383110
Durand, C.M., Betancur, C., Boeckers, T.M., Bockmann, J., Chaste, P., Fauchereau, F., et al., Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders, Nat. Genet., 2007, vol. 39, no. 1, pp. 25–27. doi 10.1038/ng1933
Ebrahimi-Fakhari, D. and Sahin, M., Autism and the synapse: Emerging mechanisms and mechanism-based therapies, Curr. Opin. Neurol., 2015, vol. 1, no. 617, pp. 1–12. doi 10.1097/WCO.0000000000000186
Ehninger, D. and Silva, A.J., Rapamycin for treating tuberous sclerosis and autism spectrum disorders, Trends Mol. Med., 2011, vol. 17, no. 2, pp. 78–87. doi 10.1016/j.molmed.2010.10.002
Ehninger, D., Han, S., Shilyansky, C., Zhou, Y., Li, W., and David, J., Reversal of learning deficits in a Tsc2+/–mouse model of tuberous sclerosis, Nat. Med., 2009, vol. 14, no. 8, pp. 843–848. doi 10.1038/nm1788.Reversal
El-Fishawy, P. and State, M.W., The genetics of autism: Key issues, recent findings, and clinical implications, Psychiatr. Clin. North Am., 2010, vol. 33, no. 1, pp. 83–105. doi 10.1016/j.psc.2009.12.002
Gadad, B.S., Li, W., Yazdani, U., Grady, S., Johnson, T., Hammond, J., et al., Administration of thimerosal-containing vaccines to infant rhesus macaques does not result in autism-like behavior or neuropathology, Proc. Natl. Acad. Sci. U.S.A., 2015, vol. 112, no. 40, pp. 12498–12503. doi 10.1073/pnas.1500968112
Ghosh, R.P., Horowitz-Scherer, R.A., Nikitina, T., Shlyakhtenko, L.S., and Woodcock, C.L., Mecp2 binds cooperatively to its substrate and competes with histone H1 for chromatin binding sites, Mol. Cell. Biol., 2010, vol. 30, no. 19, pp. 4656–4670. doi 10.1128/MCB.00379-10
Greer, P.L., Hanayama, R., Bloodgood, B.L., Mardinly, A.R., Lipton, D.M., and Flavell, S.W., The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating arc, Cell, 2010, vol. 140, no. 5, pp. 704–716. doi 10.1016/j.cell.2010.01.026
Guy, J., Hendrich, B., Holmes, M., Martin, J.E., and Bird, A., A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome, Nat. Genet., 2001, vol. 27, no. 3, pp. 322–326. doi 10.1038/85899
Hata, Y., Butz, S., and 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, vol. 16, no. 8, pp. 2488–2494. papers2://publication/uuid/43B65FDC-BC39-4EC1-8178- 47495149E5C1
Irie, M., Hata, Y., Takeuchi, M., Ichtchenko, K., Toyoda, A., Hirao, K., et al., Binding of neuroligins to PSD-95, Science, 1997, vol. 277, pp. 1511–1515. doi 10.1126/science.277.5331.1511
Jamain, S., Quach, H., Betancur, C., Råstam, M., Colineaux, C., Gillberg, I.C., et al., Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism, Nat. Genet., 2003, vol. 34, no. 1, pp. 27–29. doi 10.1038/ng1136
Jamain, S., Radyushkin, K., Hammerschmidt, K., Granon, S., Boretius, S., Varoqueaux, F., et al., Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism, Proc. Natl. Acad. Sci. U.S.A., 2008, vol. 105, no. 5, pp. 1710–1715. doi 10.1073/pnas.0711555105
Jia, F., Wang, B., Shan, L., Xu, Z., Staal, W.G., and Du, L., Core symptoms autism improved after vitamin D supplementation, Pediatrics, 2015, vol. 135, no. 1, pp. e196–e198. doi 10.1542/peds.2014-2121
Jiang, Y.H., Armstrong, D., Albrecht, U., Atkins, C.M., Noebels, J.L., Eichele, G., et al., Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation, Neuron, 1998, vol. 21, no. 4, pp. 799–811. doi 10.1016/S0896-6273(00)80596-6
Katz, D.M., Brain-derived neurotrophic factor and rett syndrome, in Handbook of Experimental Pharmacology, Lewin, G.R. and Carter, B.D., Eds., Berlin: Springer-Verlag, 2014, vol. 220, pp. 481–495. doi 10.1007/978-3-642-45106-5_18
Kelleher, R.J. and Bear, M.F., The autistic neuron: Troubled translation?, Cell, 2008, vol. 135, no. 3, pp. 401–406. doi 10.1016/j.cell.2008.10.017
Kishino, T., Lalande, M., and Wagstaff, J., UBE3A/E6-AP mutations cause Angelman syndrome, Nat. Genet., 1997, vol. 15, no. 1, pp. 70–73. doi 10.1038/ng0197-70
Kouser, M., Speed, H.E., Dewey, C.M., Reimers, J.M., Widman, A.J., Gupta, N., et al., Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission, J. Neurosci., 2013, vol. 33, no. 47, pp. 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., Pten regulates neuronal arborization social interaction in mice, Neuron, 2006, vol. 50, no. 3, pp. 377–388. doi 10.1016/j.neuron.2006.03.023
Lipton, J.O. and Sahin, M., The neurology of mTOR, Neuron, 2014, vol. 84, no. 2, pp. 275–291. doi 10.1016/j.neuron. 2014.09.034
Lisse, T.S. and Hewison, M., Vitamin D: A new player in the world of mTOR signaling, Cell Cycle, 2011, vol. 10, no. 12, pp. 1888–1889. doi 10.4161/cc.10.12.15620
Lisse, T.S., Liu, T., Irmler, M., Beckers, J., Chen, H., Adams, J.S., and 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, vol. 25, no. 3, pp. 937–947. doi 10.1096/fj.10-172577
Liu, Y., Zhang, D., and Liu, X., mTOR signaling in T cell immunity and autoimmunity, Int. Rev. Immunol., 2015, vol. 34, no. 1, pp. 50–66. doi 10.3109/08830185.2014.933957
Matsuura, T., Sutcliffe, J.S., Fang, P., Galjaard, R.J., Jiang, Y.H., Benton, C.S., et al., De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome, Nat. Genet., 1997, vol. 15, pp. 74–77. doi 10.1038/ng0197-74
Meikle, L., Pollizzi, K., Egnor, A., Kramvis, I., Lane, H., Sahin, M., and 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, vol. 28, no. 21, pp. 5422–5432. doi 10.1523/JNEUROSCI. 0955-08.2008
Missler, M. and Südhof, T.C., Neurexins: Three genes and 1001 products, Trends Genet., 1998, vol. 14, no. 1, pp. 20–26. doi 10.1016/S0168-9525(97)01324-3
Missler, M., Zhang, W., Rohlmann, A., Kattenstroth, G., Hammer, R.E., Gottmann, K., and Südhof, T.C., Alphaneurexins couple Ca2+ channels to synaptic vesicle exocytosis, Nature, 2003, vol. 423, pp. 939–948. doi 10.1038/nature01755
Okamoto, N., Kubota, T., Nakamura, Y., Murakami, R., Nishikubo, T., Tanaka, I., et al., 22q13 microduplication in two patients with common clinical manifestations: A recognizable syndrome?, Am. J. Med. Genet. Part A, 2007, vol. 143, no. 23, pp. 2804–2809. doi 10.1002/ajmg.a.31771
Pacey, L.K.K., Heximer, S.P., and Hampson, D.R., Increased GABA(B) receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures, Mol. Pharmacol., 2009, vol. 76, no. 1, pp. 18–24. doi 10.1124/mol.109.056127.posits
Peça, J., Feliciano, C., Ting, J.T., Wang, W., Wells, M.F., Venkatraman, T.N., et al., Shank3 mutant mice display autistic-like behaviours and striatal dysfunction, Nature, 2011, vol. 472, no. 7344, pp. 437–442. doi 10.1038/nature09965
Pei, J.J. and Hugon, J., mTOR-dependent signalling in Alzheimer’s disease, J. Cell. Mol. Med., 2008, vol. 12, no. 6B, pp. 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., McDermid, H., et al., 22Q13 deletion syndrome, Am. J. Med. Genet., 2001, vol. 101, no. 2, pp. 91–99. 2<91::AID-AJMG1340>3.0.CO;2-C doi 10.1002/1096-8628(20010615)101
Ricciardi, S., Boggio, E.M., Grosso, S., Lonetti, G., Forlani, G., Stefanelli, G., et al., Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model, Hum. Mol. Genet., 2011, vol. 20, no. 6, pp. 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., et al., Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome, J. Clin. Invest., 2012, vol. 122, no. 12, pp. 4544–4554. doi 10.1172/JCI61888
Roussignol, G., Ango, F., Romorini, S., Tu, J.C., Sala, C., Worley, P.F., et al., Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons, J. Neurosci., 2005, vol. 25, no. 14, pp. 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, vol. 15, no. 5, pp. 533–543. doi 10.2174/1871527315666160413120638
Segal, R.A. and Greenberg, M.E., Intracellular signaling pathways activated by neurotrophic factors, Annu. Rev. Neurosci., 1996, vol. 19, pp. 463–489. doi 10.1146/annurev.ne.19.030196.002335
Shcheglovitov, A., Shcheglovitova, O., Yazawa, M., Portmann, T., Shu, R., and Sebastiano, V., 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. and Kim, E., The Shank family of scaffold proteins, J. Cell Sci., 2000, vol. 113, no. 1, pp. 1851–1856.
Singh, S.K. and Eroglu, C., Neuroligins provide molecular links between syndromic and nonsyndromic autism, Sci. Signal, 2013, vol. 6, no. 283. doi 10.1126/scisignal.2004102
Sudhof, T.C., Neuroligins and neurexins link synaptic function to cognitive disease, Nature, 2008, vol. 455, no. 7215, pp. 903–911. 07456 doi 10.1038/nature
Tabuchi, K., Blundell, J., Etherton, M.R., Hammer, R.E., Liu, X., Powell, C.M., and Südhof, T.C., A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice, Science, 2007, vol. 318, no. 5847, pp. 71–76. doi 10.1126/science.1146221
Troca-Marin, J.A., Alves-Sampaio, A., and Montesinos, M.L., Deregulated mTOR-mediated translation in intellectual disability, Prog. Neurobiol., 2012, vol. 96, no. 2, pp. 268–282. doi 10.1016/j.pneurobio.2012.01.005
Tsai, P. and Sahin, M., Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex, Curr. Opin. Neurol., 2011, vol. 24, no. 2, pp. 106–113. doi 10.1097/WCO.0b013e32834451c4
Varoqueaux, F., Aramuni, G., Rawson, R.L., Mohrmann, R., Missler, M., Gottmann, K., et al., Neuroligins determine synapse maturation and function, Neuron, 2006, vol. 51, no. 6, pp. 741–754. doi 10.1016/j.neuron.2006.09.003
Veenstra-Vanderweele J. and Blakely, R.D., Networking in autism: Leveraging genetic, biomarker and model system findings in the search for new treatments, Neuropsychopharmacology, 2012, vol. 37, no. 1, pp. 196–212.
Wong, M., Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies, Epilepsia, 2010, vol. 51, no. 1, pp. 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., et al., mTOR plays an important role in cow’s milk allergy-associated behavioral and immunological deficits, Neuropharmacology, 2015, vol. 97, pp. 220–232. doi 10.1016/j.neuropharm.2015.04.035
Xiong, Q., Oviedo, H.V., Trotman, L.C., and Zador, A.M., PTEN regulation of local and long-range connections in mouse auditory cortex, J. Neurosci., 2012, vol. 32, no. 5, pp. 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, vol. 24, no. 4, pp. 257–272. doi 10.5607/en.2015.24.4.257
Zhou, J. and Parada, L.F., PTEN signaling in autism spectrum disorders, Curr. Opin. Neurobiol., 2012, vol. 22, no. 5, pp. 873–879. doi 10.1016/j.conb.2012.05.004
Ziemssen, T., Kumpfel, T., Klinkert, W.E.F., Neuhaus, O., and 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, vol. 125, no. 11, pp. 2381–2391. doi 10.1093/brain/awf252
Zoghbi, H.Y. and Bear, M.F., Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities, Cold Spring Harb. Perspect. Biol., 2012, vol. 4, no. 3. doi 10.1101/cshperspect.a009886
Zweier, C., de Jong, E.K., Zweier, M., Orrico, A., Ousager, L.B., Collins, A.L., et al., CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkinslike mental retardation and determine the level of a common synaptic protein in Drosophila, Am. J. Hum. Genet., 2009, vol. 85, no. 5, pp. 655–666. doi 10.1016/j.ajhg.2009.10.004
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text © E.A. Trifonova, T.M. Khlebodarova, N.E. Gruntenko, 2016, published in Vavilovskii Zhurnal Genetiki i Selektsii, 2016, Vol. 20, No. 6, pp. 959–967.
Rights and permissions
About this article
Cite this article
Trifonova, E.A., Khlebodarova, T.M. & Gruntenko, N.E. Molecular mechanisms of autism as a form of synaptic dysfunction. Russ J Genet Appl Res 7, 869–877 (2017). https://doi.org/10.1134/S2079059717080020
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S2079059717080020