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Emerging major synaptic signaling pathways involved in intellectual disability

Molecular Psychiatry volume 17, pages 682–693 (2012)Cite this article

Abstract

Genetic causes of intellectual disability (ID) include mutations in proteins with various functions. However, many of these proteins are enriched in synapses and recent investigations point out their crucial role in the subtle regulation of synaptic activity and dendritic spine morphogenesis. Moreover, in addition to genetic data, functional and animal model studies are providing compelling evidence that supports the emerging unifying synapse-based theory for cognitive deficit. In this review, we highlight ID-related gene products involved in synaptic morphogenesis and function, with a particular focus on the emergent signaling pathways involved in synaptic plasticity whose disruption results in cognitive deficit.

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References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Washington, DC, 2000.

  2. Chelly J, Khelfaoui M, Francis F, Cherif B, Bienvenu T . Genetics and pathophysiology of mental retardation. Eur J Hum Genet 2006; 14: 701–713.

    Article  CAS  PubMed  Google Scholar 

  3. Humeau Y, Gambino F, Chelly J, Vitale N . X-linked mental retardation: focus on synaptic function and plasticity. J Neurochem 2009; 109: 1–14.

    Article  CAS  PubMed  Google Scholar 

  4. Vaillend C, Poirier R, Laroche S . Genes, plasticity and mental retardation. Behav Brain Res 2008; 192: 88–105.

    Article  CAS  PubMed  Google Scholar 

  5. Purpura DP . Dendritic spine ‘dysgenesis’ and mental retardation. Science 1974; 186: 1126–1128.

    Article  CAS  PubMed  Google Scholar 

  6. Ramakers GJ . Rho proteins, mental retardation and the cellular basis of cognition. Trends Neurosci 2002; 25: 191–199.

    Article  CAS  PubMed  Google Scholar 

  7. Fiala JC, Spacek J, Harris KM . Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res Rev 2002; 39: 29–54.

    Article  PubMed  Google Scholar 

  8. Yoshihara Y, De Roo M, Muller D . Dendritic spine formation and stabilization. Curr Opin Neurobiol 2009; 19: 146–153.

    Article  CAS  PubMed  Google Scholar 

  9. Matozaki T, Nakanishi H, Takai Y . Small G-protein networks: their crosstalk and signal cascades. Cell Signal 2000; 12: 515–524.

    Article  CAS  PubMed  Google Scholar 

  10. Bergmann C, Zerres K, Senderek J, Rudnik-Schoneborn S, Eggermann T, Hausler M et al. Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain 2003; 126 (Part 7): 1537–1544.

    Article  PubMed  Google Scholar 

  11. Billuart P, Bienvenu T, Ronce N, des Portes V, Vinet MC, Zemni R et al. Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation. Nature 1998; 392: 923–926.

    Article  CAS  PubMed  Google Scholar 

  12. Philip N, Chabrol B, Lossi AM, Cardoso C, Guerrini R, Dobyns WB et al. Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia. J Med Genet 2003; 40: 441–446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zanni G, Saillour Y, Nagara M, Billuart P, Castelnau L, Moraine C et al. Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia. Neurology 2005; 65: 1364–1369.

    Article  CAS  PubMed  Google Scholar 

  14. Chabrol B, Girard N, N'Guyen K, Gérard A, Carlier M, Villard L et al. Delineation of the clinical phenotype associated with OPHN1 mutations based on the clinical and neuropsychological evaluation of three families. Am j med genet 2005; 138: 314–317.

    Article  CAS  PubMed  Google Scholar 

  15. Bedeschi MF, Novelli A, Bernardini L, Parazzini C, Bianchi V, Torres B et al. Association of syndromic mental retardation with an Xq12q13.1 duplication encompassing the oligophrenin 1 gene. Am j med genet 2008; 146A: 1718–1724.

    Article  CAS  PubMed  Google Scholar 

  16. Govek EE, Newey SE, Van Aelst L . The role of the Rho GTPases in neuronal development. Genes Dev 2005; 19: 1–49.

    Article  CAS  PubMed  Google Scholar 

  17. Tashiro A, Yuste R . Regulation of dendritic spine motility and stability by Rac1 and Rho kinase: evidence for two forms of spine motility. Mol Cell Neurosci 2004; 26: 429–440.

    Article  CAS  PubMed  Google Scholar 

  18. Khelfaoui M, Denis C, van Galen E, de Bock F, Schmitt A, Houbron C et al. Loss of X-linked mental retardation gene oligophrenin1 in mice impairs spatial memory and leads to ventricular enlargement and dendritic spine immaturity. J Neurosci 2007; 27: 9439–9450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Govek EE, Newey SE, Akerman CJ, Cross JR, Van der Veken L, Van Aelst L . The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. Nat Neurosci 2004; 7: 364–372.

    Article  CAS  PubMed  Google Scholar 

  20. Nadif Kasri N, Nakano-Kobayashi A, Malinow R, Li B, Van Aelst L . The Rho-linked mental retardation protein oligophrenin-1 controls synapse maturation and plasticity by stabilizing AMPA receptors. Genes Dev 2009; 23: 1289–1302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Khelfaoui M, Pavlowsky A, Powell AD, Valnegri P, Cheong KW, Blandin Y et al. Inhibition of RhoA pathway rescues the endocytosis defects in Oligophrenin1 mouse model of mental retardation. Hum mol genet 2009; 18: 2575–2583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nakano-Kobayashi A, Kasri NN, Newey SE, Van Aelst L . The Rho-linked mental retardation protein OPHN1 controls synaptic vesicle endocytosis via endophilin A1. Curr Biol 2009; 19: 1133–1139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Slepnev VI, De Camilli P . Accessory factors in clathrin-dependent synaptic vesicle endocytosis. Nat Rev Neurosci 2000; 1: 161–172.

    Article  CAS  PubMed  Google Scholar 

  24. Endris V, Wogatzky B, Leimer U, Bartsch D, Zatyka M, Latif F et al. The novel Rho-GTPase activating gene MEGAP/ srGAP3 has a putative role in severe mental retardation. P Natl Acad Sci USA 2002; 99: 11754–11759.

    Article  CAS  Google Scholar 

  25. Hamdan FF, Gauthier J, Pellerin S, Dobrzeniecka S, Marineau C, Fombonne E et al. No association between SRGAP3/MEGAP haploinsufficiency and mental retardation. Arch Neurol 2009; 66: 675–676.

    Article  PubMed  Google Scholar 

  26. Carlson BR, Lloyd KE, Kruszewski A, Kim IH, Rodriguiz RM, Heindel C et al. WRP/srGAP3 facilitates the initiation of spine development by an inverse F-BAR domain, and its loss impairs long-term memory. J Neurosci 2011; 31: 2447–2460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Soderling SH, Guire ES, Kaech S, White J, Zhang F, Schutz K et al. A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory. J Neurosci 2007; 27: 355–365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Orrico A, Galli L, Faivre L, Clayton-Smith J, Azzarello-Burri SM, Hertz JM et al. Aarskog-Scott syndrome: clinical update and report of nine novel mutations of the FGD1 gene. Am j med genet 2010; 152A: 313–318.

    Article  CAS  PubMed  Google Scholar 

  29. Pasteris NG, Cadle A, Logie LJ, Porteous ME, Schwartz CE, Stevenson RE et al. Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: a putative Rho/Rac guanine nucleotide exchange factor. Cell 1994; 79: 669–678.

    Article  CAS  PubMed  Google Scholar 

  30. Lebel RR, May M, Pouls S, Lubs HA, Stevenson RE, Schwartz CE . Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene. Clin Genet 2002; 61: 139–145.

    Article  CAS  PubMed  Google Scholar 

  31. Shimojima K, Sugawara M, Shichiji M, Mukaida S, Takayama R, Imai K et al. Loss-of-function mutation of collybistin is responsible for X-linked mental retardation associated with epilepsy. J Hum Genet 2011; 56: 561–565.

    Article  CAS  PubMed  Google Scholar 

  32. Harvey K, Duguid IC, Alldred MJ, Beatty SE, Ward H, Keep NH et al. The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. J Neurosci 2004; 24: 5816–5826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Papadopoulos T, Korte M, Eulenburg V, Kubota H, Retiounskaia M, Harvey RJ et al. Impaired GABAergic transmission and altered hippocampal synaptic plasticity in collybistin-deficient mice. EMBO J 2007; 26: 3888–3899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jedlicka P, Papadopoulos T, Deller T, Betz H, Schwarzacher SW . Increased network excitability and impaired induction of long-term potentiation in the dentate gyrus of collybistin-deficient mice in vivo. Mol Cell Neurosci 2009; 41: 94–100.

    Article  CAS  PubMed  Google Scholar 

  35. Reddy-Alla S, Schmitt B, Birkenfeld J, Eulenburg V, Dutertre S, Bohringer C et al. PH-domain-driven targeting of collybistin but not Cdc42 activation is required for synaptic gephyrin clustering. Eur J Neurosci 2010; 31: 1173–1184.

    Article  PubMed  Google Scholar 

  36. Poulopoulos A, Aramuni G, Meyer G, Soykan T, Hoon M, Papadopoulos T et al. Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin. Neuron 2009; 63: 628–642.

    Article  CAS  PubMed  Google Scholar 

  37. Kutsche K, Yntema H, Brandt A, Jantke I, Nothwang HG, Orth U et al. Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation. Nat genet 2000; 26: 247–250.

    Article  CAS  PubMed  Google Scholar 

  38. Missy K, Hu B, Schilling K, Harenberg A, Sakk V, Kuchenbecker K et al. AlphaPIX Rho GTPase guanine nucleotide exchange factor regulates lymphocyte functions and antigen receptor signaling. Mol cell biol 2008; 28: 3776–3789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Allen KM, Gleeson JG, Bagrodia S, Partington MW, MacMillan JC, Cerione RA et al. PAK3 mutation in nonsyndromic X-linked mental retardation. Nat genet 1998; 20: 25–30.

    Article  CAS  PubMed  Google Scholar 

  40. Bienvenu T, des Portes V, McDonell N, Carrie A, Zemni R, Couvert P et al. Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation. Am J Med Genet 2000; 93: 294–298.

    Article  CAS  PubMed  Google Scholar 

  41. Gedeon AK, Nelson J, Gecz J, Mulley JC . X-linked mild non-syndromic mental retardation with neuropsychiatric problems and the missense mutation A365E in PAK3. Am j med genet 2003; 120A: 509–517.

    Article  PubMed  Google Scholar 

  42. Peippo M, Koivisto AM, Sarkamo T, Sipponen M, von Koskull H, Ylisaukko-oja T et al. PAK3 related mental disability: further characterization of the phenotype. Am j med genet 2007; 143A: 2406–2416.

    Article  CAS  PubMed  Google Scholar 

  43. Scott RW, Olson MF . LIM kinases: function, regulation and association with human disease. J Mol Med 2007; 85: 555–568.

    Article  CAS  PubMed  Google Scholar 

  44. Arber S, Barbayannis FA, Hanser H, Schneider C, Stanyon CA, Bernard O et al. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature 1998; 393: 805–809.

    Article  CAS  PubMed  Google Scholar 

  45. Hayashi ML, Choi SY, Rao BS, Jung HY, Lee HK, Zhang D et al. Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice. Neuron 2004; 42: 773–787.

    Article  CAS  PubMed  Google Scholar 

  46. Boda B, Alberi S, Nikonenko I, Node-Langlois R, Jourdain P, Moosmayer M et al. The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. J Neurosci 2004; 24: 10816–10825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kreis P, Thevenot E, Rousseau V, Boda B, Muller D, Barnier JV . The p21-activated kinase 3 implicated in mental retardation regulates spine morphogenesis through a Cdc42-dependent pathway. J Biol Chem 2007; 282: 21497–21506.

    Article  CAS  PubMed  Google Scholar 

  48. Meng Y, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M et al. Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 2002; 35: 121–133.

    Article  CAS  PubMed  Google Scholar 

  49. Meng J, Meng Y, Hanna A, Janus C, Jia Z . Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3. J Neurosci 2005; 25: 6641–6650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Node-Langlois R, Muller D, Boda B . Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. J Cell Sci 2006; 119 (Part 23): 4986–4993.

    Article  CAS  PubMed  Google Scholar 

  51. Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med 2009; 360: 599–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kim JH, Liao D, Lau LF, Huganir RL . SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 1998; 20: 683–691.

    Article  CAS  PubMed  Google Scholar 

  53. Tarpey P, Parnau J, Blow M, Woffendin H, Bignell G, Cox C et al. Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation. Am J Hum Genet 2004; 75: 318–324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sheng M, Sala C . PDZ domains and the organization of supramolecular complexes. Annu rev neurosci 2001; 24: 1–29.

    Article  CAS  PubMed  Google Scholar 

  55. Zanni G, van Esch H, Bensalem A, Saillour Y, Poirier K, Castelnau L et al. A novel mutation in the DLG3 gene encoding the synapse-associated protein 102 (SAP102) causes non-syndromic mental retardation. Neurogenetics 2010; 11: 251–255.

    Article  CAS  PubMed  Google Scholar 

  56. Cuthbert PC, Stanford LE, Coba MP, Ainge JA, Fink AE, Opazo P et al. Synapse-associated protein 102/dlgh3 couples the NMDA receptor to specific plasticity pathways and learning strategies. J Neurosci 2007; 27: 2673–2682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kim JH, Lee HK, Takamiya K, Huganir RL . The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. J Neurosci 2003; 23: 1119–1124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Komiyama NH, Watabe AM, Carlisle HJ, Porter K, Charlesworth P, Monti J et al. SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J Neurosci 2002; 22: 9721–9732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Vazquez LE, Chen HJ, Sokolova I, Knuesel I, Kennedy MB . SynGAP regulates spine formation. J Neurosci 2004; 24: 8862–8872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Qin Y, Zhu Y, Baumgart JP, Stornetta RL, Seidenman K, Mack V et al. State-dependent Ras signaling and AMPA receptor trafficking. Genes Dev 2005; 19: 2000–2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Carlisle HJ, Manzerra P, Marcora E, Kennedy MB . SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin. J Neurosci 2008; 28: 13673–13683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kim MJ, Dunah AW, Wang YT, Sheng M . Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron 2005; 46: 745–760.

    Article  CAS  PubMed  Google Scholar 

  63. Sans N, Petralia RS, Wang YX, Blahos II J, Hell JW, Wenthold RJ . A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J Neurosci 2000; 20: 1260–1271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Trivier E, De Cesare D, Jacquot S, Pannetier S, Zackai E, Young I et al. Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 1996; 384: 567–570.

    Article  CAS  PubMed  Google Scholar 

  65. Sassone-Corsi P, Mizzen CA, Cheung P, Crosio C, Monaco L, Jacquot S et al. Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science 1999; 285: 886–891.

    Article  CAS  PubMed  Google Scholar 

  66. Xing J, Ginty DD, Greenberg ME . Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 1996; 273: 959–963.

    Article  CAS  PubMed  Google Scholar 

  67. Pereira PM, Schneider A, Pannetier S, Heron D, Hanauer A . Coffin-Lowry syndrome. Eur J Hum Genet 2010; 18: 627–633.

    Article  CAS  PubMed  Google Scholar 

  68. Poirier R, Jacquot S, Vaillend C, Soutthiphong AA, Libbey M, Davis S et al. Deletion of the Coffin-Lowry syndrome gene Rsk2 in mice is associated with impaired spatial learning and reduced control of exploratory behavior. Behav Genet 2007; 37: 31–50.

    Article  CAS  PubMed  Google Scholar 

  69. Mehmood T, Schneider A, Sibille J, Marques Pereira P, Pannetier S, Ammar MR et al. Transcriptome profile reveals AMPA receptor dysfunction in the hippocampus of the Rsk2-knockout mice, an animal model of Coffin-Lowry syndrome. Hum Genet 2011; 129: 255–269.

    Article  CAS  PubMed  Google Scholar 

  70. Zeniou-Meyer M, Begle A, Bader MF, Vitale N . The Coffin-Lowry syndrome-associated protein RSK2 controls neuroendocrine secretion through the regulation of phospholipase D1 at the exocytotic sites. Ann N Y Acad Sci 2009; 1152: 201–208.

    Article  CAS  PubMed  Google Scholar 

  71. Zeniou-Meyer M, Liu Y, Begle A, Olanich ME, Hanauer A, Becherer U et al. The Coffin-Lowry syndrome-associated protein RSK2 is implicated in calcium-regulated exocytosis through the regulation of PLD1. P Natl Acad Sci USA 2008; 105: 8434–8439.

    Article  CAS  Google Scholar 

  72. D'Adamo P, Menegon A, Lo Nigro C, Grasso M, Gulisano M, Tamanini F et al. Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nature genetics 1998; 19: 134–139.

    Article  CAS  PubMed  Google Scholar 

  73. Giannandrea M, Bianchi V, Mignogna ML, Sirri A, Carrabino S, D'Elia E et al. Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet 2010; 86: 185–195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Corbett MA, Bahlo M, Jolly L, Afawi Z, Gardner AE, Oliver KL et al. A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am J Hum Genet 2010; 87: 371–375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Falace A, Filipello F, La Padula V, Vanni N, Madia F, De Pietri Tonelli D et al. TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am J Hum Genet 2010; 87: 365–370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bianchi V, Farisello P, Baldelli P, Meskenaite V, Milanese M, Vecellio M et al. Cognitive impairment in Gdi1-deficient mice is associated with altered synaptic vesicle pools and short-term synaptic plasticity, and can be corrected by appropriate learning training. Hum Mol Genet 2009; 18: 105–117.

    Article  CAS  PubMed  Google Scholar 

  77. Donaldson JG . Multiple roles for Arf6: sorting, structuring, and signaling at the plasma membrane. J Biol Chem 2003; 278: 41573–41576.

    Article  CAS  PubMed  Google Scholar 

  78. D'Souza-Schorey C, Chavrier P . ARF proteins: roles in membrane traffic and beyond. Nat Rev Mol Cell Biol 2006; 7: 347–358.

    Article  CAS  PubMed  Google Scholar 

  79. Funakoshi Y, Hasegawa H, Kanaho Y . Regulation of PIP5K activity by Arf6 and its physiological significance. J Cell Physiol 2011; 226: 888–895.

    Article  CAS  PubMed  Google Scholar 

  80. Jaworski J . ARF6 in the nervous system. Eur J Cell Biol 2007; 86: 513–524.

    Article  CAS  PubMed  Google Scholar 

  81. Scholz R, Berberich S, Rathgeber L, Kolleker A, Kohr G, Kornau HC . AMPA receptor signaling through BRAG2 and Arf6 critical for long-term synaptic depression. Neuron 2010; 66: 768–780.

    Article  CAS  PubMed  Google Scholar 

  82. Sanda M, Kamata A, Katsumata O, Fukunaga K, Watanabe M, Kondo H et al. The postsynaptic density protein, IQ-ArfGEF/BRAG1, can interact with IRSp53 through its proline-rich sequence. Brain Res 2009; 1251: 7–15.

    Article  CAS  PubMed  Google Scholar 

  83. Sakagami H, Sanda M, Fukaya M, Miyazaki T, Sukegawa J, Yanagisawa T et al. IQ-ArfGEF/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses. Neurosci Res 2008; 60: 199–212.

    Article  CAS  PubMed  Google Scholar 

  84. Shoubridge C, Tarpey PS, Abidi F, Ramsden SL, Rujirabanjerd S, Murphy JA et al. Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability. Nat genet 2010; 42: 486–488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Shoubridge C, Walikonis RS, Gecz J, Harvey RJ . Subtle functional defects in the Arf-specific guanine nucleotide exchange factor IQSEC2 cause non-syndromic X-linked intellectual disability. Small Gtpases 2010; 1: 98–103.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Carrie A, Jun L, Bienvenu T, Vinet MC, McDonell N, Couvert P et al. A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nat genet 1999; 23: 25–31.

    Article  CAS  PubMed  Google Scholar 

  87. Bahi N, Friocourt G, Carrie A, Graham ME, Weiss JL, Chafey P et al. IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. Hum Mol Genet 2003; 12: 1415–1425.

    Article  CAS  PubMed  Google Scholar 

  88. Pavlowsky A, Gianfelice A, Pallotto M, Zanchi A, Vara H, Khelfaoui M et al. A postsynaptic signaling pathway that may account for the cognitive defect due to IL1RAPL1 mutation. Curr Biol 2010; 20: 103–115.

    Article  CAS  PubMed  Google Scholar 

  89. Piton A, Michaud J, Peng H, Aradhya S, Gauthier J, Mottron L et al. Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum Mol Genet 2008; 17: 3965–3974.

    Article  CAS  PubMed  Google Scholar 

  90. Nawara M, Klapecki J, Borg K, Jurek M, Moreno S, Tryfon J et al. Novel mutation of IL1RAPL1gene in a nonspecific X-linked mental retardation (MRX) family. Am J Med Genet 2008; 146A: 3167–3172.

    Article  PubMed  Google Scholar 

  91. Tabolacci E, Pomponi MG, Pietrobono R, Terracciano A, Chiurazzi P, Neri G . A truncating mutation in the IL1RAPL1 gene is responsible for X-linked mental retardation in the MRX21 family. Am j med genet 2006; 140: 482–487.

    Article  CAS  PubMed  Google Scholar 

  92. Gambino F, Pavlowsky A, Begle A, Dupont JL, Bahi N, Courjaret R et al. IL1-receptor accessory protein-like 1 (IL1RAPL1), a protein involved in cognitive functions, regulates N-type Ca2+-channel and neurite elongation. P Natl Acad Sci USA 2007; 104: 9063–9068.

    Article  CAS  Google Scholar 

  93. Handley MT, Lian LY, Haynes LP, Burgoyne RD . Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder. PLoS One 2010; 5: e10534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kim MJ, Futai K, Jo J, Hayashi Y, Cho K, Sheng M . Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95. Neuron 2007; 56: 488–502.

    Article  CAS  PubMed  Google Scholar 

  95. Born TL, Smith DE, Garka KE, Renshaw BR, Bertles JS, Sims JE . Identification and characterization of two members of a novel class of the interleukin-1 receptor (IL-1R) family. Delineation Of a new class of IL-1R-related proteins based on signaling. J Biol Chem 2000; 275: 41528.

    Article  CAS  PubMed  Google Scholar 

  96. Khan JA, Brint EK, O'Neill LA, Tong L . Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL. J Biol Chem 2004; 279: 31664–31670.

    Article  CAS  PubMed  Google Scholar 

  97. Thomas G, Lin D, Nuriya M, Huganir R . Rapid and bi-directional regulation of AMPA receptor phosphorylation and trafficking by JNK. EMBO J 2008; 27: 361–372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Pavlowsky A, Zanchi A, Pallotto M, Giustetto M, Chelly J, Sala C et al. Neuronal JNK pathway activation by IL-1 is mediated through IL1RAPL1, a protein required for development of cognitive functions. Commun Integr Biol 2010; 3: 245–247.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Rothwell NJ, Luheshi GN . Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci 2000; 23: 618–625.

    Article  CAS  PubMed  Google Scholar 

  100. Ross FM, Allan SM, Rothwell NJ, Verkhratsky A . A dual role for interleukin-1 in LTP in mouse hippocampal slices. J Neuroimmunol 2003; 144: 61–67.

    Article  CAS  PubMed  Google Scholar 

  101. Avital A, Goshen I, Kamsler A, Segal M, Iverfeldt K, Richter-Levin G et al. Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. Hippocampus 2003; 13: 826–834.

    Article  CAS  PubMed  Google Scholar 

  102. Goshen I, Kreisel T, Ounallah-Saad H, Renbaum P, Zalzstein Y, Ben-Hur T et al. A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 2007; 32: 1106–1115.

    Article  CAS  PubMed  Google Scholar 

  103. Sudhof TC . Neuroligins and neurexins link synaptic function to cognitive disease. Nature 2008; 455: 903–911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Chubykin AA, Atasoy D, Etherton MR, Brose N, Kavalali ET, Gibson JR et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 2007; 54: 919–931.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Etherton M, Foldy C, Sharma M, Tabuchi K, Liu X, Shamloo M et al. Autism-linked neuroligin-3 R451C mutation differentially alters hippocampal and cortical synaptic function. P Natl Acad Sci USA 2011; 108: 13764–13769.

    Article  CAS  Google Scholar 

  106. Costa RM, Federov NB, Kogan JH, Murphy GG, Stern J, Ohno M et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 2002; 415: 526–530.

    Article  CAS  PubMed  Google Scholar 

  107. Li W, Cui Y, Kushner SA, Brown RA, Jentsch JD, Frankland PW et al. The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol 2005; 15: 1961–1967.

    Article  CAS  PubMed  Google Scholar 

  108. Shilyansky C, Lee YS, Silva AJ . Molecular and cellular mechanisms of learning disabilities: a focus on NF1. Annu rev neurosci 2010; 33: 221–243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bowerman M, Beauvais A, Anderson CL, Kothary R . Rho-kinase inactivation prolongs survival of an intermediate SMA mouse model. Hum Mol Genet 2010; 19: 1468–1478.

    Article  CAS  PubMed  Google Scholar 

  110. Barman SA, Zhu S, White RE . RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension. Vasc Health Risk Manag 2009; 5: 663–671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Calo LA, Pessina AC . RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans. J Hypertens 2007; 25: 259–264.

    Article  CAS  PubMed  Google Scholar 

  112. Dong M, Yan BP, Liao JK, Lam YY, Yip GW, Yu CM . Rho-kinase inhibition: a novel therapeutic target for the treatment of cardiovascular diseases. Drug Discov Today 2010; 15: 622–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Daouti S, Wang H, Li WH, Higgins B, Kolinsky K, Packman K et al. Characterization of a novel mitogen-activated protein kinase kinase 1/2 inhibitor with a unique mechanism of action for cancer therapy. Cancer Res 2009; 69: 1924–1932.

    Article  CAS  PubMed  Google Scholar 

  114. Messersmith WA, Hidalgo M, Carducci M, Eckhardt SG . Novel targets in solid tumors: MEK inhibitors. Clin Adv Hematol Oncol 2006; 4: 831–836.

    PubMed  Google Scholar 

  115. Diana G, Valentini G, Travaglione S, Falzano L, Pieri M, Zona C et al. Enhancement of learning and memory after activation of cerebral Rho GTPases. P Natl Acad Sci USA 2007; 104: 636–641.

    Article  CAS  Google Scholar 

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Acknowledgements

PB and JC are supported by ANR (ANR-08-MNPS-037-04, ANR 2010-Neuro-001-01, ANR-2010-BLAN-1434-03), European Union (Gencodys, FP7 241995), Fondation Jérôme Lejeune and INSERM. AP was supported by the ‘Ministère de l'Education Nationale’ and SUNY. We thank P van de Nes and B Lee for their help with the English.

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  1. A Pavlowsky

    Present address: 4Current address: A Pavlowsky, PhD, SUNY Downstate Medical Center, Department of Pathology, 450 Clarkson Ave, Box 25, Brooklyn, 11203 NY, USA.,

  2. J Chelly

    Present address: 5Current address: J Chelly, Pr, PhD, Institut Cochin, Department of Genetic and Development, 24 rue du Fg St Jacques, 75014, Paris, France.,

  3. P Billuart

    Present address: 6Current address: P Billuart, PharmD, PhD, Institut Cochin, Department of Genetic and Development, 24 rue du Fg St Jacques, 75014, Paris, France.,

Authors and Affiliations

  1. Department of Genetic and Development, Institut Cochin, Université Paris Descartes, CNRS, UMR8104, Paris, France

    A Pavlowsky, J Chelly & P Billuart

  2. INSERM, U1016, Paris, France

    A Pavlowsky, J Chelly & P Billuart

  3. Department of Pathology, State University of New York Downstate Medical Center, Brooklyn, NY, USA

    A Pavlowsky

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  1. A Pavlowsky
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Correspondence to P Billuart.

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Pavlowsky, A., Chelly, J. & Billuart, P. Emerging major synaptic signaling pathways involved in intellectual disability. Mol Psychiatry 17, 682–693 (2012). https://doi.org/10.1038/mp.2011.139

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