Synapse dysfunction in autism: A molecular medicine approach to drug discovery in neurodevelopmental disorders

Trends in Pharmacological Sciences

Volumn 33, Issue 12, 2012, Pages 669-684

  Spooren, Will ^a   Lindemann, Lothar ^a   Ghosh, Anirvan ^a   Santarelli, Luca ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; AMANTADINE; ARBACLOFEN; ATOMOXETINE; BUSPIRONE; CITALOPRAM; CYCLOSERINE; DIAZEPAM; FLUOXETINE; GALANTAMINE; GLUTAMATE RECEPTOR; GLUTAMATE RECEPTOR 5 ANTAGONIST; GLUTAMATE RECEPTOR ANTAGONIST; GUANFACINE; LAMOTRIGINE; MAMMALIAN TARGET OF RAPAMYCIN; MEMANTINE; METHYLPHENIDATE; MINOCYCLINE; NEUROFIBROMIN; OCTAHYDRO 4 HYDROXY 4 [(3 METHYLPHENYL)ETHYNYL] 1H INDOLE 1 CARBOXYLIC ACID METHYL ESTER; PALIPERIDONE; PIOGLITAZONE; RILUZOLE; RISPERIDONE; RO 4917523; SECRETIN; STX 107; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZIPRASIDONE;

AUTISM; BEHAVIOR DISORDER; CELL ADHESION; CLINICAL FEATURE; DEVELOPMENTAL DISORDER; DIAGNOSTIC ACCURACY; DIAGNOSTIC TEST; DIFFERENTIAL DIAGNOSIS; DRUG RESEARCH; DRUG TARGETING; DSM-IV; FRAGILE X SYNDROME; GENE PRODUCT; GENETIC LINKAGE; HUMAN; ICD-10; INCIDENCE; MICROBIOLOGY; MOLECULAR BIOLOGY; MOLECULAR GENETICS; MONOGENIC DISORDER; NERVOUS SYSTEM DEVELOPMENT; NEUROLOGIC DISEASE; NONHUMAN; OCCUPATIONAL THERAPY; PATHOPHYSIOLOGY; PERSONALIZED MEDICINE; PHENOTYPE; PHYSIOTHERAPY; PREVALENCE; PRIORITY JOURNAL; PROTEIN TARGETING; PSYCHOTHERAPY; RETT SYNDROME; REVIEW; RISK BENEFIT ANALYSIS; RISK FACTOR; SEIZURE; SPECIAL EDUCATION; SPEECH THERAPY; SPERMATOGENESIS; SYMPTOM; SYNAPSE DYSFUNCTION;

ANIMALS; AUTISTIC DISORDER; CHILD; CHILD DEVELOPMENT DISORDERS, PERVASIVE; DRUG DISCOVERY; HUMANS; PSYCHOTROPIC DRUGS; SYNAPSES;

EID: 84869213888     PISSN: 01656147     EISSN: 18733735     Source Type: Journal    
DOI: 10.1016/j.tips.2012.09.004     Document Type: Review

References (116)

1. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 4th edn, text revision; DSM-IVTR 2000 American Psychiatric Publishing
2. World Health Organization ICD-10: Version 2010 2010 WHO
3. H. Faras Autism spectrum disorders Ann. Saudi Med. 30 2010 295 300
4. C.P. Johnson Identification and evaluation of children with autism spectrum disorders Pediatrics 120 2007 1183 1215
5. S.E. Levy Autism Lancet 374 2009 1627 1638
6. T. Charman, and G. Baird Practitioner review: diagnosis of autism spectrum disorder in 2- and 3-year-old children J. Child Psychol. Psychiatry 43 2002 289 305
7. J. Humphries Autism: recognising the signs in young children Prof. Care Mother Child 8 1998 127 130
8. I. Rapin, and R.F. Tuchman Autism: definition, neurobiology, screening, diagnosis Pediatr. Clin. North Am. 55 2008 1129 1146
9. S. Chakrabarti Early identification of autism Indian Pediatr. 46 2009 412 414
10. C. Lord The autism diagnostic observation schedule - generic: a standard measure of social and communication deficits associated with the spectrum of autism J. Autism Dev. Disord. 30 2000 205 223
11. A. Le Couteur Autism diagnostic interview: a standardized investigator-based instrument J. Autism Dev. Disord. 19 1989 363 387
12. V. Lotter Epidemiology of autistic conditions in young children Soc. Psychiatry 1 1966 124 135
13. G. Baird Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP) Lancet 368 2006 210 215
14. S. Baron-Cohen Why are autism spectrum conditions more prevalent in males? PLoS Biol. 9 2011 e1001081
15. C. Rice Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, United States, 2006 MMWR Surveill. Summ. 58 2009 1 20
16. M. Knapp Economic cost of autism in the UK Autism 13 2009 317 336
17. S.M. Myers, and C.P. Johnson Management of children with autism spectrum disorders Pediatrics 120 2007 1162 1182
18. Z. Warren Therapies for Children with Autism Spectrum Disorders 2011 Comparative Effectiveness Review No. 26, US Agency for Healthcare Research and Quality
19. D. Malhotra, and J. Sebat CNVs: harbingers of a rare variant revolution in psychiatric genetics Cell 148 2012 1223 1241
20. G. Horev Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism Proc. Natl. Acad. Sci. U.S.A. 108 2011 17076 17081
21. S.J. Sanders De novo mutations revealed by whole-exome sequencing are strongly associated with autism Nature 485 2012 237 241
22. M. State, and P. Levitt The conundrums of understanding genetic risks for autism spectrum disorders Nat. Neurosci. 14 2011 1499 1506
23. B.R. Bill, and D.H. Geschwind Genetic advances in autism: heterogeneity and convergence on shared pathways Curr. Opin. Genet. Dev. 19 2009 271 278
24. R.A. Kumar, and S.L. Christian Genetics of autism spectrum disorders Curr. Neurol. Neurosci. Rep. 9 2009 188 197
25. C. Ecker Translational approaches to the biology of autism: false dawn or a new era? Mol. Psychiatry 2012 10.1038/mp.2012.102
26. S. Jamain Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism Nat. Genet. 34 2003 27 29
27. B.S. Abrahams, and D.H. Geschwind Advances in autism genetics: on the threshold of a new neurobiology Nat. Rev. Genet. 9 2008 341 355
28. G. Roussignol Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons J. Neurosci. 25 2005 3560 3570
29. A.Y. Hung Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1 J. Neurosci. 28 2008 1697 1708
30. C. Betancur The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders Trends Neurosci. 32 2009 402 412
31. S.C. Vernes A functional genetic link between distinct developmental language disorders N. Engl. J. Med. 359 2008 2337 2345
32. E.M. Morrow Identifying autism loci and genes by tracing recent shared ancestry Science 321 2008 218 223
33. K. Wang Common genetic variants on 5p14.1 associate with autism spectrum disorders Nature 459 2009 528 533
34. T. Marui Association of the neuronal cell adhesion molecule (NRCAM) gene variants with autism Int. J. Neuropsychopharmacol. 12 2009 1 10
35. S. Monfort Detection of known and novel genomic rearrangements by array based comparative genomic hybridisation: deletion of ZNF533 and duplication of CHARGE syndrome genes J. Med. Genet. 45 2008 432 437
36. W.T. O'Donnell, and S.T. Warren A decade of molecular studies of fragile X syndrome Annu. Rev. Neurosci. 25 2002 315 338
37. J.C. Darnell FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism Cell 146 2011 247 261
38. B.E. Pfeiffer, and K.M. Huber The state of synapses in fragile X syndrome Neuroscientist 15 2009 549 567
39. D.D. Krueger, and M.F. Bear Toward fulfilling the promise of molecular medicine in fragile X syndrome Annu. Rev. Med. 62 2011 411 429
40. J. Levenga Potential therapeutic interventions for fragile X syndrome Trends Mol. Med. 16 2010 516 527
41. E. Berry-Kravis Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial J. Child Adolesc. Psychopharmacol. 16 2006 525 540
42. T.V. Bilousova Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model J. Med. Genet. 46 2009 94 102
43. M. Bear The mGluR theory of fragile X mental retardation Trends Neurosci. 27 2004 370 377
44. F.M.S. de Vrij Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice Neurobiol. Dis. 31 2008 127 132
45. G. Dolen Correction of fragile X syndrome in mice Neuron 56 2007 955 962
46. A. Michalon Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice Neuron 74 2012 49 56
47. M. Chahrour, and H.Y. Zoghbi The story of Rett syndrome: from clinic to neurobiology Neuron 56 2007 422 437
48. K.K. Gadalla MeCP2 and Rett syndrome: reversibility and potential avenues for therapy Biochem. J. 439 2011 1 14
49. J. Guy The role of MeCP2 in the brain Annu. Rev. Cell Dev. Biol. 27 2011 631 652
50. R.C. Samaco, and J.L. Neul Complexities of Rett syndrome and MeCP2 J. Neurosci. 31 2011 7951 7959
51. A.K. Percy Rett syndrome: exploring the autism link Arch. Neurol. 68 2011 985 989
52. L. Medrihan Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome J. Neurophysiol. 99 2008 112 121
53. V.S. Dani Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome Proc. Natl. Acad. Sci. U.S.A. 102 2005 12560 12565
54. J.C. Roux Tyrosine hydroxylase deficit in the chemoafferent and the sympathoadrenergic pathways of the Mecp2 deficient mouse Neurosci. Lett. 447 2008 82 86
55. Y. Asaka Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome Neurobiol. Dis. 21 2006 217 227
56. E.M. Boggio Synaptic determinants of Rett syndrome Front. Synaptic Neurosci. 2 2010 28
57. J. Guy Reversal of neurological defects in a mouse model of Rett syndrome Science 315 2007 1143 1147
58. E. Giacometti Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2 Proc. Natl. Acad. Sci. U.S.A. 104 2007 1931 1936
59. A.L. Collins Mild overexpression of MeCP2 causes a progressive neurological disorder in mice Hum. Mol. Genet. 13 2004 2679 2689
60. Q. Chang The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression Neuron 49 2006 341 348
61. D. Tropea Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice Proc. Natl. Acad. Sci. U.S.A. 106 2009 2029 2034
62. K.P. Boyd Neurofibromatosis type 1 J. Am. Acad. Dermatol. 61 2009 1 14
63. V.C. Williams Neurofibromatosis type 1 revisited Pediatrics 123 2009 124 133
64. W. Li The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1 Curr. Biol. 15 2005 1961 1967
65. R.M. Costa Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1 Nature 415 2002 526 530
66. P. Curatolo Tuberous sclerosis Lancet 372 2008 657 668
67. R. White Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers Ann. Neurol. 49 2001 67 78
68. L. Meikle 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. 28 2008 5422 5432
69. +/- mouse model of tuberous sclerosis Nat. Med. 14 2008 843 848
70. B.D. Auerbach Mutations causing syndromic autism define an axis of synaptic pathophysiology Nature 480 2011 63 68
71. Ehninger, D. From genes to cognition in tuberous sclerosis: implications for mTOR inhibitor-based treatment approaches. Neuropharmacology, (in press)
72. D. Ehninger, and A.J. Silva Rapamycin for treating tuberous sclerosis and autism spectrum disorders Trends Mol. Med. 17 2011 78 87
73. M.G. Butler Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations J. Med. Genet. 42 2005 318 321
74. E.J. Hong Transcriptional control of cognitive development Curr. Opin. Neurobiol. 15 2005 21 28
75. E.O. Williams Delta protocadherin 10 is regulated by activity in the mouse main olfactory system Front. Neural Circuits 5 2011 9
76. G.D. Gilfillan SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome Am. J. Hum. Genet. 82 2008 1003 1010
77. B.G. Van, and J.P. Fryns Angelman syndrome (AS, MIM 105830) Eur. J. Hum. Genet. 17 2009 1367 1373
78. A. Aziz DIA1R is an X-linked gene related to deleted in autism-1 PLoS ONE 6 2011 e14534
79. C.L. Waites, and C.C. Garner Presynaptic function in health and disease Trends Neurosci. 34 2011 326 337
80. T.A. Blanpied, and M.D. Ehlers Microanatomy of dendritic spines: emerging principles of synaptic pathology in psychiatric and neurological disease Biol. Psychiatry 55 2004 1121 1127
81. M.E. Pitulescu, and R.H. Adams Eph/ephrin molecules - a hub for signaling and endocytosis Genes Dev. 24 2010 2480 2492
82. C.M. Durand Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders Nat. Genet. 39 2007 25 27
83. R. Moessner Contribution of SHANK3 mutations to autism spectrum disorder Am. J. Hum. Genet. 81 2007 1289 1297
84. A.M. Grabrucker Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies Trends Cell Biol. 21 2011 594 603
85. O. Bozdagi Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication Mol. Autism 1 2010 15
86. M. Yang Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice J. Neurosci. 32 2012 6525 6541
87. S.S. Margolis EphB-mediated degradation of the RhoA GEF ephexin5 relieves a developmental brake on excitatory synapse formation Cell 143 2010 442 455
88. B.E. Pfeiffer Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2 Neuron 66 2010 191 197
89. M. van Spronsen, and C.C. Hoogenraad Synapse pathology in psychiatric and neurologic disease Curr. Neurol. Neurosci. Rep. 10 2010 207 214
90. H.T. Chao MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number Neuron 56 2007 58 65
91. P. Moretti Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome J. Neurosci. 26 2006 319 327
92. R.D. Smrt Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons Neurobiol. Dis. 27 2007 77 89
93. C.A. Chapleau Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations Neurobiol. Dis. 35 2009 219 233
94. R. Pizzarelli, and E. Cherubini Alterations of GABAergic signaling in autism spectrum disorders Neural Plast. 2011 2011 297153
95. G.G. Turrigiano, and S.B. Nelson Homeostatic plasticity in the developing nervous system Nat. Rev. Neurosci. 5 2004 97 107
96. J.L.R. Rubenstein, and M.M. Merzenich Model of autism: increased ratio of excitation/inhibition in key neural systems Genes Brain Behav. 2 2003 255 267
97. J.P. Hussman Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism J. Autism Dev. Disord. 31 2001 247 248
98. D.F. Owens, and A.R. Kriegstein Is there more to GABA than synaptic inhibition? Nat. Rev. Neurosci. 3 2002 715 727
99. Z.J. Huang Development of GABA innervation in the cerebral and cerebellar cortices Nat. Rev. Neurosci. 8 2007 673 686
100. R. Tyzio The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal neurons is sequential and correlates with the development of the apical dendrite J. Neurosci. 19 1999 10372 10382
101. T.C. Südhof Neuroligins and neurexins link synaptic function to cognitive disease Nature 455 2008 903 911
102. A. Brooks-Kayal Epilepsy and autism spectrum disorders: are there common developmental mechanisms? Brain Dev. 32 2010 731 738
103. L. Rooms, and R.F. Kooy Advances in understanding fragile X syndrome and related disorders Curr. Opin. Pediatr. 23 2011 601 606
104. A. Poulopoulos Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin Neuron 63 2009 628 642
105. C.M. Niswender, and P.J. Conn Metabotropic glutamate receptors: physiology, pharmacology, and disease Annu. Rev. Pharmacol. Toxicol. 50 2010 295 322
106. K.M. Huber Altered synaptic plasticity in a mouse model of fragile X mental retardation Proc. Natl. Acad. Sci. U.S.A. 99 2002 7746 7750
107. J.L. Silverman Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism Sci. Transl. Med. 4 2012 131ra51
108. M.V. Mehta mGluR5-antagonist mediated reversal of elevated stereotyped, repetitive behaviors in the VPA model of autism PLoS ONE 6 2011 e26077
109. W. Spooren Insight into the function of group I and group II metabotropic glutamate (mGlu) receptors: behavioural characterization and implications for the treatment of CNS disorders Behav. Pharmacol. 14 2003 257 277
110. L. Lindemann CTEP: a novel, potent, long-acting, and orally bioavailable metabotropic glutamate receptor 5 inhibitor J. Pharmacol. Exp. Ther. 339 2011 474 486
111. M.B. Dalva Ephecting excitatory synapse development Cell 143 2010 341 342
112. C.J. Newschaffer The epidemiology of autism spectrum disorders Annu. Rev. Public Health 28 2007 235 258
113. F.R. Volkmar, and D. Pauls Autism Lancet 362 2003 1133 1141
114. M. Knapp The Economic Consequences of Autism in the UK 2007 Foundation for People with Learning Disabilities
115. L.K. Wink Emerging drugs for the treatment of symptoms associated with autism spectrum disorders Expert Opin. Emerg. Drugs 15 2010 481 494
116. D.Z. Wetmore, and C.C. Garner Emerging pharmacotherapies for neurodevelopmental disorders J. Dev. Behav. Pediatr. 31 2010 564 581