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Synaptic Dysfunction and Intellectual Disability

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Part of the book series: Advances in Experimental Medicine and Biology ((volume 970))

Abstract

Intellectual disability (ID) is a common and highly heterogeneous paediatric disorder with a very severe social impact. Intellectual disability can be caused by environmental and/or genetic factors. Although in the last two decades a number of genes have been discovered whose mutations cause mental retardation, we are still far from identifying the impact of these mutations on brain functions. Many of the genes mutated in ID code for several proteins with a variety of functions: chromatin remodelling, pre-/post-synaptic activity, and intracellular trafficking. The prevailing hypothesis suggests that the ID phenotype could emerge from abnormal cellular processing leading to pre- and/or post-synaptic dysfunction. In this chapter, we focus on the role of small GTPases and adhesion molecules, and we discuss the mechanisms through which they lead to synaptic network dysfunction.

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References

  • Allen, K. M., Gleeson, J. G., Bagrodia, S., Partington, M. W., MacMillan, J. C., Cerione, R. A., Mulley, J. C., & Walsh, C. A. (1998). PAK3 mutation in nonsyndromic X-linked mental retardation. Nature Genetics, 20, 25–30.

    Article  PubMed  CAS  Google Scholar 

  • Arendt, T., Gärtner, U., Seeger, G., Barmashenko, G., Palm, K., Mittmann, T., Yan, L., Hümmeke, M., Behrbohm, J., Brückner, M. K., Holzer, M., Wahle, P., & Heumann, R. (2004). Neuronal activation of Ras regulates synaptic connectivity. European Journal of Neuroscience, 19, 2953–2966.

    Article  PubMed  Google Scholar 

  • Bahi, N., Friocourt, G., Carrie, A., Graham, M. E., Weiss, J. L., Chafey, P., Fauchereau, F., Burgoyne, R. D., & Chelly, J. (2003). IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. Human Molecular Genetics, 12, 1415–1425.

    Article  PubMed  CAS  Google Scholar 

  • Bernstein, B. W., & Bamburg, J. R. (2010). ADF/cofilin: A functional node in cell biology. Trends in Cell Biology, 20, 187–195.

    Article  PubMed  CAS  Google Scholar 

  • Bienvenu, T., des Portes, V., McDonell, N., Carrié, A., Zemni, R., Couvert, P., Ropers, H. H., Moraine, C., van Bokhoven, H., Fryns, J. P., Allen, K., Walsh, C. A., Boué, J., Kahn, A., Chelly, J., & Beldjord, C. (2000). Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation. American Journal of Medical Genetics, 93, 294–298.

    Article  PubMed  CAS  Google Scholar 

  • Blanpied, T. A., & Ehlers, M. D. (2004). Microanatomy of dendritic spines: Emerging principles of synaptic pathology in psychiatric and neurological disease. Biological Psychiatry, 55, 1121–1127.

    Article  PubMed  Google Scholar 

  • Blundell, J., Blaiss, C. A., Etherton, M. R., Espinosa, F., Tabuchi, K., Walz, C., Bolliger, M. F., Südhof, T. C., & Powell, C. M. (2010). Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. Journal of Neuroscience, 30, 2115–2129.

    Article  PubMed  CAS  Google Scholar 

  • Boda, B., Alberi, S., Nikonenko, I., Node-Langlois, R., Jourdain, P., Moosmayer, M., Parisi-Jourdain, L., & Muller, D. (2004). The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. Journal of Neuroscience, 24, 10816–10825.

    Article  PubMed  CAS  Google Scholar 

  • Boda, B., Dubos, A., & Muller, D. (2010). Signaling mechanisms regulating synapse formation and function in mental retardation. Current Opinion in Neurobiology, 20, 519–527.

    Article  PubMed  CAS  Google Scholar 

  • Boda, B., Jourdain, L., & Muller, D. (2008). Distinct, but compensatory roles of PAK1 and PAK3 in spine morphogenesis. Hippocampus, 18, 857–861.

    Article  PubMed  CAS  Google Scholar 

  • Bokoch, G. M. (2003). Biology of the p21-activated kinases. Annual Review of Biochemistry, 72, 743–781.

    Article  PubMed  CAS  Google Scholar 

  • Boulet, S. L., Schieve, L. A., & Boyle, C. A. (2009). Birth weight and health and developmental outcomes in US children, 1997–2005. Matern Child Health Journal. 2011. Oct:15(7):836–44. doi:10.1007/s10995-009-0538-2.

  • Bradley, E. A., Thompson, A., & Bryson, S. E. (2002). Mental retardation in teenagers: Prevalence data from the Niagara region, Ontario. Canadian Journal of Psychiatry, 47, 652–659.

    Google Scholar 

  • Carrie, A., et al. (1999). A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nature Genetics, 23, 25–31.

    PubMed  CAS  Google Scholar 

  • Chadman, K. K., Gong, S., Scattoni, M. L., Boltuck, S. E., Gandhy, S. U., Heintz, N., & Crawley, J. N. (2008). Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Research, 1, 147–158.

    Article  PubMed  Google Scholar 

  • Chocholska, S., Rossier, E., Barbi, G., & Kehrer-Sawatzki, H. (2006). Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2-22.3 with a highly variable phenotype in female carriers. American Journal of Medical Genetics A, 140, 604–610.

    Article  CAS  Google Scholar 

  • Comoletti, D., De Jaco, A., Jennings, L. L., Flynn, R. E., Gaietta, G., Tsigelny, I., Ellisman, M. H., & Taylor, P. (2004). The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. Journal of Neuroscience, 24, 4889–4893.

    Article  PubMed  CAS  Google Scholar 

  • D’Hulst, C., & Kooy, R. F. (2009). Fragile X syndrome: From molecular genetics to therapy. Journal of Medical Genetics, 46, 577–584.

    Article  PubMed  CAS  Google Scholar 

  • Dalva, M. B., McClelland, A. C., & Kayser, M. S. (2007). Cell adhesion molecules: Signalling functions at the synapse. Nature Reviews Neuroscience, 8, 206–220.

    Article  PubMed  CAS  Google Scholar 

  • De Jaco, A., Lin, M. Z., Dubi, N., Comoletti, D., Miller, M. T., Camp, S., Ellisman, M., Butko, M. T., Tsien, R. Y., & Taylor, P. (2010). Neuroligin trafficking deficiencies arising from mutations in the alpha/beta-hydrolase fold protein family. The Journal of Biological Chemistry, 285, 28674–28682.

    Article  PubMed  CAS  Google Scholar 

  • Dean, C., & Dresbach, T. (2006). Neuroligins and neurexins: Linking cell adhesion, synapse formation and cognitive function. Trends in Neurosciences, 29, 21–29.

    Article  PubMed  CAS  Google Scholar 

  • Doussau, F., Gasman, S., Humeau, Y., Vitiello, F., Popoff, M., Boquet, P., Bader, M. F., & Poulain, B. (2000). A Rho-related GTPase is involved in Ca(2+)-dependent neurotransmitter exocytosis. The Journal of Biological Chemistry, 275, 7764–7770.

    Article  PubMed  CAS  Google Scholar 

  • Drews, C. D., Yeargin-Allsopp, M., Decouflé, P., & Murphy, C. C. (1995). Variation in the influence of selected sociodemographic risk factors for mental retardation. American Journal of Public Health, 85, 329–334.

    Article  PubMed  CAS  Google Scholar 

  • Ehninger, D., Li, W., Fox, K., Stryker, M. P., & Silva, A. J. (2008). Reversing neurodevelopmental disorders in adults. Neuron, 60, 950–960.

    Article  PubMed  CAS  Google Scholar 

  • Endris, V., Wogatzky, B., Leimer, U., Bartsch, D., Zatyka, M., Latif, F., Maher, E. R., Tariverdian, G., Kirsch, S., Karch, D., & Rappold, G. A. (2002). The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental retardation. Proceedings of the National Academy of Sciences of the United States of America, 99, 11754–11759.

    Article  PubMed  CAS  Google Scholar 

  • Eng, C. (2003). PTEN: One gene, many syndromes. Human Mutation, 22, 183–198.

    Article  PubMed  CAS  Google Scholar 

  • Feng, J., Schroer, R., Yan, J., Song, W., Yang, C., Bockholt, A., Cook, E. H., Skinner, C., Schwartz, C. E., & Sommer, S. S. (2006). High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neuroscience Letters, 409, 10–13.

    Article  PubMed  CAS  Google Scholar 

  • Fiala, J. C., Spacek, J., & Harris, K. M. (2002). Dendritic spine pathology: Cause or consequence of neurological disorders? Brain Research: Brain Research Reviews, 39, 29–54.

    Article  PubMed  Google Scholar 

  • Fu, Z., Lee, S. H., Simonetta, A., Hansen, J., Sheng, M., & Pak, D. T. (2007). Differential roles of Rap1 and Rap2 small GTPases in neurite retraction and synapse elimination in hippocampal spiny neurons. Journal of Neurochemistry, 100, 118–131.

    Article  PubMed  CAS  Google Scholar 

  • Gäddlin, P. O., Finnström, O., Sydsjö, G., & Leijon, I. (2009). Most very low birth weight subjects do well as adults. Acta Paediatrica, 98, 1513–1520.

    Article  PubMed  Google Scholar 

  • Gambino, F., Pavlowsky, A., Béglé, A., Dupont, J. L., Bahi, N., Courjaret, R., Gardette, R., Hadjkacem, H., Skala, H., Poulain, B., Chelly, J., Vitale, N., & Humeau, Y. (2007). IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca2+-channel and neurite elongation. Proceedings of the National Academy of Sciences of the United States of America, 104, 9063–9068.

    Article  PubMed  CAS  Google Scholar 

  • Govek, E. E., Newey, S. E., Akerman, C. J., Cross, J. R., Van der Veken, L., & Van Aelst, L. (2004). The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nature Neuroscience, 7, 364–372.

    Article  PubMed  CAS  Google Scholar 

  • Govek, E. E., Newey, S. E., & Van Aelst, L. (2005). The role of the Rho GTPases in neuronal development. Genes and Development, 19, 1–49.

    Article  PubMed  CAS  Google Scholar 

  • Gu, Y., & Stornetta, R. L. (2007). Synaptic plasticity, AMPA-R trafficking, and Ras-MAPK signaling. Acta Pharmacologica Sinica, 28, 928–936.

    Article  PubMed  CAS  Google Scholar 

  • Hamdan, F. F., et al. (2009). Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. The New England Journal of Medicine, 360, 599–605.

    Article  PubMed  CAS  Google Scholar 

  • Hishimoto, A., Liu, Q. R., Drgon, T., Pletnikova, O., Walther, D., Zhu, X. G., Troncoso, J. C., & Uhl, G. R. (2007). Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms. Human Molecular Genetics, 16, 2880–2891.

    Article  PubMed  CAS  Google Scholar 

  • Hu, H., Qin, Y., Bochorishvili, G., Zhu, Y., van Aelst, L., & Zhu, J. J. (2008). Ras signaling mechanisms underlying impaired GluR1-dependent plasticity associated with fragile X syndrome. Journal of Neuroscience, 28, 7847–7862.

    Article  PubMed  CAS  Google Scholar 

  • Humeau, Y., Gambino, F., Chelly, J., & Vitale, N. (2009). X-linked mental retardation: Focus on synaptic function and plasticity. Journal of Neurochemistry, 109, 1–14.

    Article  PubMed  CAS  Google Scholar 

  • Iida, J., Ishizaki, H., Okamoto-Tanaka, M., Kawata, A., Sumita, K., Ohgake, S., Sato, Y., Yorifuji, H., Nukina, N., Ohashi, K., Mizuno, K., Tsutsumi, T., Mizoguchi, A., Miyoshi, J., Takai, Y., & Hata, Y. (2007). Synaptic scaffolding molecule alpha is a scaffold to mediate N-methyl-D-aspartate receptor-dependent RhoA activation in dendrites. Molecular and Cellular Biology, 27, 4388–4405.

    Article  PubMed  CAS  Google Scholar 

  • Jaffe, A. B., & Hall, A. (2005). Rho GTPases: Biochemistry and biology. Annual Review of Cell and Developmental Biology, 21, 247–269.

    Article  PubMed  CAS  Google Scholar 

  • Jaffer, Z. M., & Chernoff, J. (2002). p21-activated kinases: Three more join the Pak. The International Journal of Biochemistry and Cell Biology, 34, 713–717.

    Article  CAS  Google Scholar 

  • Jamain, S., Quach, H., Betancur, C., Rastam, M., Colineaux, C., Gillberg, I. C., Soderstrom, H., Giros, B., Leboyer, M., Gillberg, C., & Bourgeron, T. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34, 27–29.

    Article  PubMed  CAS  Google Scholar 

  • Jamain, S., Radyushkin, K., Hammerschmidt, K., Granon, S., Boretius, S., Varoqueaux, F., Ramanantsoa, N., Gallego, J., Ronnenberg, A., Winter, D., Frahm, J., Fischer, J., Bourgeron, T., Ehrenreich, H., & Brose, N. (2008). Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proceedings of the National Academy of Sciences of the United States of America, 105, 1710–1715.

    Article  PubMed  CAS  Google Scholar 

  • Kandel, E. R. (2001). The molecular biology of memory storage: A dialogue between genes and synapses. Science, 294, 1030–1038.

    Article  PubMed  CAS  Google Scholar 

  • Kaufman, L., Ayub, M., & Vincent, J. B. (2010). The genetic basis of non-syndromic intellectual disability: A review. Journal of Neurodevelopmental Disorders, 2, 182–209.

    Article  PubMed  Google Scholar 

  • Kaufmann, W. E., & Moser, H. W. (2000). Dendritic anomalies in disorders associated with mental retardation. Cerebral Cortex, 10, 981–991.

    Article  PubMed  CAS  Google Scholar 

  • Kessels, H. W., & Malinow, R. (2009). Synaptic AMPA receptor plasticity and behavior. Neuron, 61, 340–350.

    Article  PubMed  CAS  Google Scholar 

  • Khelfaoui, M., Denis, C., van Galen, E., de Bock, F., Schmitt, A., Houbron, C., Morice, E., Giros, B., Ramakers, G., Fagni, L., Chelly, J., Nosten-Bertrand, M., & Billuart, P. (2007). Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. Journal of Neuroscience, 27, 9439–9450.

    Article  PubMed  CAS  Google Scholar 

  • Khelfaoui, M., Pavlowsky, A., Powell, A. D., Valnegri, P., Cheong, K. W., Blandin, Y., Passafaro, M., Jefferys, J. G., Chelly, J., & Billuart, P. (2009). Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation. Human Molecular Genetics, 18, 2575–2583.

    Article  PubMed  CAS  Google Scholar 

  • Kim, M. J., Dunah, A. W., Wang, Y. T., & Sheng, M. (2005). Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron, 46, 745–760.

    Article  PubMed  CAS  Google Scholar 

  • Kim, J. H., Liao, D., Lau, L. F., & Huganir, R. L. (1998). SynGAP: A synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron, 20, 683–691.

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. G., et al. (2008). Disruption of neurexin 1 associated with autism spectrum disorder. American Journal of Human Genetics, 82, 199–207.

    Article  PubMed  CAS  Google Scholar 

  • Kirov, G., Gumus, D., Chen, W., Norton, N., Georgieva, L., Sari, M., O’Donovan, M. C., Erdogan, F., Owen, M. J., Ropers, H. H., & Ullmann, R. (2008). Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Human Molecular Genetics, 17, 458–465.

    Article  PubMed  CAS  Google Scholar 

  • Krapivinsky, G., Medina, I., Krapivinsky, L., Gapon, S., & Clapham, D. E. (2004). SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron, 43, 563–574.

    Article  PubMed  CAS  Google Scholar 

  • Kutsche, K., Yntema, H., Brandt, A., Jantke, I., Nothwang, H. G., Orth, U., Boavida, M. G., David, D., Chelly, J., Fryns, J. P., Moraine, C., Ropers, H. H., Hamel, B. C., van Bokhoven, H., & Gal, A. (2000). Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nature Genetics, 26, 247–250.

    Article  PubMed  CAS  Google Scholar 

  • Lachman, H. M., Fann, C. S., Bartzis, M., Evgrafov, O. V., Rosenthal, R. N., Nunes, E. V., Miner, C., Santana, M., Gaffney, J., Riddick, A., Hsu, C. L., & Knowles, J. A. (2007). Genomewide suggestive linkage of opioid dependence to chromosome 14q. Human Molecular Genetics, 16, 1327–1334.

    Article  PubMed  CAS  Google Scholar 

  • Laumonnier, F., Bonnet-Brilhault, F., Gomot, M., Blanc, R., David, A., Moizard, M. P., Raynaud, M., Ronce, N., Lemonnier, E., Calvas, P., Laudier, B., Chelly, J., Fryns, J. P., Ropers, H. H., Hamel, B. C., Andres, C., Barthélémy, C., Moraine, C., & Briault, S. (2004). X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. American Journal of Human Genetics, 74, 552–557.

    Article  PubMed  CAS  Google Scholar 

  • Lawson-Yuen, A., Saldivar, J. S., Sommer, S., & Picker, J. (2008). Familial deletion within NLGN4 associated with autism and Tourette syndrome. European Journal of Human Genetics, 16, 614–618.

    Article  PubMed  CAS  Google Scholar 

  • Leonard, H., & Wen, X. (2002). The epidemiology of mental retardation: Challenges and opportunities in the new millennium. Mental Retardation and Developmental Disabilities Research Reviews, 8, 117–134.

    Article  PubMed  Google Scholar 

  • Levitt, P., & Campbell, D. B. (2009). The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. The Journal of Clinical Investigation, 119, 747–754.

    Article  PubMed  CAS  Google Scholar 

  • Lonze, B. E., & Ginty, D. D. (2002). Function and regulation of CREB family transcription factors in the nervous system. Neuron, 35, 605–623.

    Article  PubMed  CAS  Google Scholar 

  • Macarov, M., Zeigler, M., Newman, J. P., Strich, D., Sury, V., Tennenbaum, A., & Meiner, V. (2007). Deletions of VCX-A and NLGN4: A variable phenotype including normal intellect. Journal of Intellectual Disability Research, 51, 329–333.

    Article  PubMed  CAS  Google Scholar 

  • Marshall, C. R., et al. (2008). Structural variation of chromosomes in autism spectrum disorder. American Journal of Human Genetics, 82, 477–488.

    Article  PubMed  CAS  Google Scholar 

  • May, P. A., & Gossage, J. P. (2001). Estimating the prevalence of fetal alcohol syndrome: A summary. Alcohol Research and Health, 25, 159–167.

    PubMed  CAS  Google Scholar 

  • McLaren, J., & Bryson, S. E. (1987). Review of recent epidemiological studies of mental retardation: Prevalence, associated disorders, and etiology. American Journal of Mental Retardation, 92, 243–254.

    PubMed  CAS  Google Scholar 

  • Meng, J., Meng, Y., Hanna, A., Janus, C., & Jia, Z. (2005). Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3. Journal of Neuroscience, 25, 6641–6650.

    Article  PubMed  CAS  Google Scholar 

  • Meng, Y., Zhang, Y., Tregoubov, V., Janus, C., Cruz, L., Jackson, M., Lu, W. Y., MacDonald, J. F., Wang, J. Y., Falls, D. L., & Jia, Z. (2002). Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron, 35, 121–133.

    Article  PubMed  CAS  Google Scholar 

  • Moon, S. Y., & Zheng, Y. (2003). Rho GTPase-activating proteins in cell regulation. Trends in Cell Biology, 13, 13–22.

    Article  PubMed  CAS  Google Scholar 

  • Morrow, E. M., et al. (2008). Identifying autism loci and genes by tracing recent shared ancestry. Science, 321, 218–223.

    Article  PubMed  CAS  Google Scholar 

  • Muddashetty, R. S., Kelić, S., Gross, C., Xu, M., & Bassell, G. J. (2007). Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome. Journal of Neuroscience, 27, 5338–5348.

    Article  PubMed  CAS  Google Scholar 

  • Nadif Kasri, N., & Van Aelst, L. (2008). Rho-linked genes and neurological disorders. Pflügers Archiv, 455, 787–797.

    Article  PubMed  CAS  Google Scholar 

  • Nakano-Kobayashi, A., Kasri, N. N., Newey, S. E., & Van Aelst, L. (2009). The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1. Current Biology, 19, 1133–1139.

    Article  PubMed  CAS  Google Scholar 

  • Nasu-Nishimura, Y., Hayashi, T., Ohishi, T., Okabe, T., Ohwada, S., Hasegawa, Y., Senda, T., Toyoshima, C., Nakamura, T., & Akiyama, T. (2006). Role of the Rho GTPase-activating protein RICS in neurite outgrowth. Genes to Cells, 11, 607–614.

    Article  PubMed  CAS  Google Scholar 

  • Newey, S. E., Velamoor, V., Govek, E. E., & Van Aelst, L. (2005). Rho GTPases, dendritic structure, and mental retardation. Journal of Neurobiology, 64, 58–74.

    Article  PubMed  CAS  Google Scholar 

  • Niccols, A. (2007). Fetal alcohol syndrome and the developing socio-emotional brain. Brain and Cognition, 65, 135–142.

    Article  PubMed  Google Scholar 

  • Nimchinsky, E. A., Sabatini, B. L., & Svoboda, K. (2002). Structure and function of dendritic spines. Annual Review of Physiology, 64, 313–353.

    Article  PubMed  CAS  Google Scholar 

  • Nodé-Langlois, R., Muller, D., & Boda, B. (2006). Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. Journal of Cell Science, 119, 4986–4993.

    Article  PubMed  CAS  Google Scholar 

  • Orloff, M. S., & Eng, C. (2008). Genetic and phenotypic heterogeneity in the PTEN hamartoma tumour syndrome. Oncogene, 27, 5387–5397.

    Article  PubMed  CAS  Google Scholar 

  • Pak, D. T., Yang, S., Rudolph-Correia, S., Kim, E., & Sheng, M. (2001). Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP. Neuron, 31, 289–303.

    Article  PubMed  CAS  Google Scholar 

  • Pavlowsky, A., Gianfelice, A., Pallotto, M., Zanchi, A., Vara, H., Khelfaoui, M., Valnegri, P., Rezai, X., Bassani, S., Brambilla, D., Kumpost, J., Blahos, J., Roux, M. J., Humeau, Y., Chelly, J., Passafaro, M., Giustetto, M., Billuart, P., & Sala, C. (2010). A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation. Current Biology, 20, 103–115.

    Article  PubMed  CAS  Google Scholar 

  • Pfeiffer, B. E., & Huber, K. M. (2009). The state of synapses in fragile X syndrome. The Neuroscientist, 15, 549–567.

    Article  PubMed  CAS  Google Scholar 

  • Pinto, D., et al. (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature, 466, 368–372.

    Article  PubMed  CAS  Google Scholar 

  • Purpura, D. P. (1974). Dendritic spine “dysgenesis” and mental retardation. Science, 186, 1126–1128.

    Article  PubMed  CAS  Google Scholar 

  • Rauch, A., Hoyer, J., Guth, S., Zweier, C., Kraus, C., Becker, C., Zenker, M., Hüffmeier, U., Thiel, C., Rüschendorf, F., Nürnberg, P., Reis, A., & Trautmann, U. (2006). Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. American Journal of Medical Genetics A, 140, 2063–2074.

    Article  Google Scholar 

  • Reeve, S. P., Bassetto, L., Genova, G. K., Kleyner, Y., Leyssen, M., Jackson, F. R., & Hassan, B. A. (2005). The Drosophila fragile X mental retardation protein controls actin dynamics by directly regulating profilin in the brain. Current Biology, 15, 1156–1163.

    Article  PubMed  CAS  Google Scholar 

  • Rex, C. S., Chen, L. Y., Sharma, A., Liu, J., Babayan, A. H., Gall, C. M., & Lynch, G. (2009). Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. The Journal of Cell Biology, 186, 85–97.

    Article  PubMed  CAS  Google Scholar 

  • Roberts, A., Allanson, J., Jadico, S. K., Kavamura, M. I., Noonan, J., Opitz, J. M., Young, T., & Neri, G. (2006). The cardiofaciocutaneous syndrome. Journal of Medical Genetics, 43, 833–842.

    Article  PubMed  CAS  Google Scholar 

  • Roeleveld, N., Zielhuis, G. A., & Gabreëls, F. (1997). The prevalence of mental retardation: A critical review of recent literature. Developmental Medicine and Child Neurology, 39, 125–132.

    Article  PubMed  CAS  Google Scholar 

  • Ropers, H. H. (2010). Genetics of early onset cognitive impairment. Annual Review of Genomics and Human Genetics, 11, 161–187.

    Article  PubMed  CAS  Google Scholar 

  • Ropers, H. H., & Hamel, B. C. (2005). X-linked mental retardation. Nature Reviews Genetics, 6, 46–57.

    Article  PubMed  CAS  Google Scholar 

  • Rosenberger, G., Jantke, I., Gal, A., & Kutsche, K. (2003). Interaction of alphaPIX (ARHGEF6) with beta-parvin (PARVB) suggests an involvement of alphaPIX in integrin-mediated signaling. Human Molecular Genetics, 12, 155–167.

    Article  PubMed  CAS  Google Scholar 

  • Rumbaugh, G., Adams, J. P., Kim, J. H., & Huganir, R. L. (2006). SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proceedings of the National Academy of Sciences of the United States of America, 103, 4344–4351.

    Article  PubMed  CAS  Google Scholar 

  • Ryu, J., Futai, K., Feliu, M., Weinberg, R., & Sheng, M. (2008). Constitutively active Rap2 transgenic mice display fewer dendritic spines, reduced extracellular signal-regulated kinase signaling, enhanced long-term depression, and impaired spatial learning and fear extinction. Journal of Neuroscience, 28, 8178–8188.

    Article  PubMed  CAS  Google Scholar 

  • Schubbert, S., Bollag, G., & Shannon, K. (2007). Deregulated Ras signaling in developmental disorders: New tricks for an old dog. Current Opinion in Genetics and Development, 17, 15–22.

    Article  PubMed  CAS  Google Scholar 

  • Seidman, L. J., Buka, S. L., Goldstein, J. M., Horton, N. J., Rieder, R. O., & Tsuang, M. T. (2000). The relationship of prenatal and perinatal complications to cognitive functioning at age 7 in the New England Cohorts of the National Collaborative Perinatal Project. Schizophrenia Bulletin, 26, 309–321.

    Article  PubMed  CAS  Google Scholar 

  • Soderling, S. H., Guire, E. S., Kaech, S., White, J., Zhang, F., Schutz, K., Langeberg, L. K., Banker, G., Raber, J., & Scott, J. D. (2007). A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory. Journal of Neuroscience, 27, 355–365.

    Article  PubMed  CAS  Google Scholar 

  • Spohr, H. L., Willms, J., & Steinhausen, H. C. (2007). Fetal alcohol spectrum disorders in young adulthood. The Journal of Pediatrics, 150, 175–179, 179.e171.

    Article  PubMed  CAS  Google Scholar 

  • Stanyon, C. A., & Bernard, O. (1999). LIM-kinase1. The International Journal of Biochemistry and Cell Biology, 31, 389–394.

    Article  CAS  Google Scholar 

  • Südhof, T. C. (2008). Neuroligins and neurexins link synaptic function to cognitive disease. Nature, 455, 903–911.

    Article  PubMed  CAS  Google Scholar 

  • Szatmari, P., et al. (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39, 319–328.

    Article  PubMed  CAS  Google Scholar 

  • Tabuchi, K., Blundell, J., Etherton, M. R., Hammer, R. E., Liu, X., Powell, C. M., & Südhof, T. C. (2007). A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science, 318, 71–76.

    Article  PubMed  CAS  Google Scholar 

  • Tada, T., & Sheng, M. (2006). Molecular mechanisms of dendritic spine morphogenesis. Current Opinion in Neurobiology, 16, 95–101.

    Article  PubMed  CAS  Google Scholar 

  • Talebizadeh, Z., Lam, D. Y., Theodoro, M. F., Bittel, D. C., Lushington, G. H., & Butler, M. G. (2006). Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. Journal of Medical Genetics, 43, e21.

    Article  PubMed  CAS  Google Scholar 

  • Tassabehji, M., Metcalfe, K., Fergusson, W. D., Carette, M. J., Dore, J. K., Donnai, D., Read, A. P., Pröschel, C., Gutowski, N. J., Mao, X., & Sheer, D. (1996). LIM-kinase deleted in Williams syndrome. Nature Genetics, 13, 272–273.

    Article  PubMed  CAS  Google Scholar 

  • Thomas, G. M., & Huganir, R. L. (2004). MAPK cascade signalling and synaptic plasticity. Nature Reviews Neuroscience, 5, 173–183.

    Article  PubMed  CAS  Google Scholar 

  • Thomas, G. M., Lin, D. T., Nuriya, M., & Huganir, R. L. (2008). Rapid and bi-directional regulation of AMPA receptor phosphorylation and trafficking by JNK. EMBO Journal, 27, 361–372.

    Article  PubMed  CAS  Google Scholar 

  • Threadgill, R., Bobb, K., & Ghosh, A. (1997). Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron, 19, 625–634.

    Article  PubMed  CAS  Google Scholar 

  • Walsh, T., et al. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science, 320, 539–543.

    Article  PubMed  CAS  Google Scholar 

  • Wu, F., Chen, Y., Li, Y., Ju, J., Wang, Z., & Yan, D. (2008). RNA-interference-mediated Cdc42 silencing down-regulates phosphorylation of STAT3 and suppresses growth in human 100. bladder-cancer cells. Biotechnology and Applied Biochemistry, 49, 121–128.

    Article  PubMed  CAS  Google Scholar 

  • Wu, G. Y., Deisseroth, K., & Tsien, R. W. (2001). Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology. Nature Neuroscience, 4, 151–158.

    Article  PubMed  CAS  Google Scholar 

  • Yan, J., Feng, J., Schroer, R., Li, W., Skinner, C., Schwartz, C. E., Cook, E. H., & Sommer, S. S. (2008a). Analysis of the neuroligin 4Y gene in patients with autism. Psychiatric Genetics, 18, 204–207.

    Article  PubMed  Google Scholar 

  • Yan, J., Noltner, K., Feng, J., Li, W., Schroer, R., Skinner, C., Zeng, W., Schwartz, C. E., & Sommer, S. S. (2008b). Neurexin 1alpha structural variants associated with autism. Neuroscience Letters, 438, 368–370.

    Article  PubMed  CAS  Google Scholar 

  • Yan, Y., Yang, D., Zarnowska, E. D., Du, Z., Werbel, B., Valliere, C., Pearce, R. A., Thomson, J. A., & Zhang, S. C. (2005). Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells, 23, 781–790.

    Article  PubMed  CAS  Google Scholar 

  • Zahir, F. R., Baross, A., Delaney, A. D., Eydoux, P., Fernandes, N. D., Pugh, T., Marra, M. A., & Friedman, J. M. (2008). A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha. Journal of Medical Genetics, 45, 239–243.

    Article  PubMed  CAS  Google Scholar 

  • Zalfa, F., Eleuteri, B., Dickson, K. S., Mercaldo, V., De Rubeis, S., di Penta, A., Tabolacci, E., Chiurazzi, P., Neri, G., Grant, S. G., & Bagni, C. (2007). A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability. Nature Neuroscience, 10, 578–587.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, Y., Pak, D., Qin, Y., McCormack, S. G., Kim, M. J., Baumgart, J. P., Velamoor, V., Auberson, Y. P., Osten, P., van Aelst, L., Sheng, M., & Zhu, J. J. (2005). Rap2-JNK removes synaptic AMPA receptors during depotentiation. Neuron, 46, 905–916.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, J. J., Qin, Y., Zhao, M., Van Aelst, L., & Malinow, R. (2002). Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell, 110, 443–455.

    Article  PubMed  CAS  Google Scholar 

  • Zhu, X., Raina, A. K., Perry, G., & Smith, M. A. (2004). Alzheimer’s disease: The two-hit hypothesis. Lancet Neurology, 3, 219–226.

    Article  PubMed  CAS  Google Scholar 

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Valnegri, P., Sala, C., Passafaro, M. (2012). Synaptic Dysfunction and Intellectual Disability. In: Kreutz, M., Sala, C. (eds) Synaptic Plasticity. Advances in Experimental Medicine and Biology, vol 970. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0932-8_19

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