Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid

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• 作者：Chiara Nicolini (1)
  Younghee Ahn (2)
  Bernadeta Michalski (1)
  Jong M Rho (2)
  Margaret Fahnestock (1)
  
• 关键词：Human postmortem ; Autism ; Valproate ; Signal transduction ; TrkB ; PSD ; 95
• 刊名：Acta Neuropathologica Communications
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：3
• 期：1
• 全文大小：1,455 KB
• 参考文献：1. American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Press, Washington, DC
  2. Kelleher RJ 3rd, Bear MF (2008) The autistic neuron: troubled translation? Cell 135:401鈥?06 CrossRef
  3. Troca-Marin JA, Alves-Sampaio A, Montesinos ML (2012) Deregulated mTOR-mediated translation in intellectual disability. Prog Neurobiol 96:268鈥?82 CrossRef
  4. Levitt P, Campbell DB (2009) The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. J Clin Invest 119:747鈥?54 CrossRef
  5. Ehninger D, Silva AJ (2011) Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders. Trends Mol Med 17:78鈥?7 molmed.2010.10.002" target="_blank" title="It opens in new window">CrossRef
  6. Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB et al (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493:371鈥?77 CrossRef
  7. Hutsler JJ, Zhang H (2010) Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res 1309:83鈥?4 CrossRef
  8. L枚scher V (2002) Basic pharmacology of valproate. A review after 35聽years of clinical use for the treatment of epilepsy. CNS Drugs 16:669鈥?94 CrossRef
  9. Lambert PA, Carraz G, Borselli S, Bouchardy M (1975) Dipropylacetamide in the treatment of manic-depressive psychosis. Enc茅phale 1:25鈥?1
  10. Emrich HM, von Zerssen D, Kissling W, M枚ller HG, Windorfer A (1980) Effect of sodium valproate on mania. The GABA-hypothesis of affective disorders. Acta Psychiatr Nervenkr 229:1鈥?6 CrossRef
  11. Christianson AL, Chesler N, Kromberg JG (1994) Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs. Dev Med Child Neurol 36:361鈥?69 CrossRef
  12. Moore SJ, Turnpenny P, Quinn A, Glover S, Lloyd DJ, Montgomery T et al (2000) A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 37:489鈥?97 mg.37.7.489" target="_blank" title="It opens in new window">CrossRef
  13. Christensen J, Gronborg TK, Sorensen MJ, Schendel D, Parner ET, Pedersen LH et al (2013) Prenatal exposure and risk of autism spectrum disorders and childhood autism. JAMA 309:1696鈥?703 ma.2013.2270" target="_blank" title="It opens in new window">CrossRef
  14. Markram H, Rinaldi T, Markram K (2007) The intense world syndrome- an alternative hypothesis for autism. Front Neurosci 1:77鈥?6 CrossRef
  15. Stanton ME, Peloso E, Brown KL, Rodier P (2007) Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism. Behav Brain Res 176:133鈥?40 CrossRef
  16. Roulett FI, Wollaston L, Decatanzaro D, Foster JA (2010) Behavioural and molecular changes in the mouse in response to prenatal exposure to the anti-epileptic drug valproic acid. Neuroscience 170:514鈥?22 CrossRef
  17. Kataoka S, Takuma K, Hara Y, Maeda Y, Ago Y, Matsuda T (2013) Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol 16:91鈥?03 CrossRef
  18. Schneider T, Przewlocki R (2005) Behavioural alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30:80鈥?9 CrossRef
  19. Markram K, Rinaldi T, La Mendola D, Sandi C, Markram H (2008) Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology 33:901鈥?12 CrossRef
  20. Rodier PM, Ingram JL, Tisdale B, Croog VJ (1997) Linking etiologies in humans and animal models: studies of autism. Reprod Toxicol 11:417鈥?22 CrossRef
  21. Ingram JL, Peckham SM, Tisdale B, Rodier PM (2000) Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 22:319鈥?24 CrossRef
  22. Narita N, Kato M, Tazoe M, Miyazaki K, Narita M, Okado N (2002) Increased monoamine concentration in the brain and blood of fetal thalidomide- and valproic acid-exposed rat: putative animal models for autism. Pediatr Res 52:576鈥?79
  23. Kolozsi E, Mackenzie RN, Roulett FI, deCatanzaro D, Foster JA (2009) Prenatal exposure to valproic acid leads to reduced expression of synptic adhesion molecule neuroligin 3 in mice. Neuroscience 163:1201鈥?210 CrossRef
  24. Rinaldi T, Silberberg G, Markram H (2008) Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid. Cereb Cortex 18:763鈥?70 m117" target="_blank" title="It opens in new window">CrossRef
  25. Rinaldi T, Perrodin C, Markram H (2008) Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic acid animal model of autism. Front Neural Circuits 2:4 CrossRef
  26. Schanen NC (2006) Epigenetics of autism spectrum disorders. Hum Mol Genet 2:138鈥?50 mg/ddl213" target="_blank" title="It opens in new window">CrossRef
  27. Wong CC, Meaburn EL, Ronald A, Price TS, Jeffries AR, Schwalkwyk LC et al (2014) Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol Psychiatry 19:495鈥?03 mp.2013.41" target="_blank" title="It opens in new window">CrossRef
  28. Garcia KLP, Guanhua Y, Nicolini C, Michalski B, Garzon D, Chiu VS et al (2012) Altered balance of proteolytic forms of pro-brain-derived neurotrophic factor in autism. J Neuropathol Exp Neurol 71:289鈥?97 CrossRef
  29. Boucher J, Lewis V (1992) Unfamiliar face recognition in relatively able autistic children. J Child Psychol Psychiatry 33:843鈥?59 CrossRef
  30. Allison T, Ginter H, McCarthy G, Nobre AC, Puce A, Luby M et al (1994) Face recognition in human extrastriate cortex. J Neurophysiol 71:821鈥?25
  31. Gauthier I, Anderson AW, Tarr MJ, Skudlarski P, Gore JC (1997) Levels of categorization in visual recognition studied using functional magnetic resonance imaging. Curr Biol 7:645鈥?51 CrossRef
  32. Schultz RT, Gauthier I, Klin A, Fulbright RK, Anderson AW, Volkmar F et al (2000) Abnormal ventral temporal cortical activity during face discrimination among individuals with autism and Asperger syndrome. Arch Gen Psychiatry 57:331鈥?40 CrossRef
  33. Lord C, Rutter M, Le Couteur A (1994) Autism diagnostic interview-revised. A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Autism Dev Dis 24:659鈥?85 CrossRef
  34. Chomiak T, Karnik V, Block E, Hu B (2010) Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism. BMC Neurosci 11:102 CrossRef
  35. Menna E, Zambetti S, Morini R, Donzelli A, Disanza A, Calvigioni D et al (2013) Eps8 controls dendritic spine density and synaptic plasticity through its actin-capping activity. EMBO J 32:1730鈥?744 mboj.2013.107" target="_blank" title="It opens in new window">CrossRef
  36. Ricciardi S, Boggio EM, Grosso S, Lonetti G, Forlani G, Stefanelli G et al (2011) Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet 20:1182鈥?196 mg/ddq563" target="_blank" title="It opens in new window">CrossRef
  37. Yoshii A, Constantine-Paton M (2010) Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev Neurobiol 70:304鈥?22
  38. Newcombe J, Woodroofe MN, Cuzner ML (1986) Distribution of glial fibrillary acidic protein in gliosed human white matter. J Neurochem 47:1713鈥?719 CrossRef
  39. Fatemi SH, Folsom TD (2011) Dysregulation of fragile X mental retardation protein and metabotropic glutamate receptor 5 in superior frontal cortex of individuals with autism: a postmortem brain study. Mol Autism 2:6 CrossRef
  40. Bourgeron T (2009) A synaptic trek to autism. Curr Opin Neurobiol 19:231鈥?34 CrossRef
  41. Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 33:67鈥?5 CrossRef
  42. Sheikh AM, Malik M, Wen G, Chauhan A, Chauhan V, Gong CX et al (2010) BDNF-Akt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. J Neurosci Res 88:2641鈥?647
  43. Zoghbi HY, Bear MF (2012) Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb Perspect Biol 4(3):a009886 CrossRef
  44. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926鈥?945 CrossRef
  45. Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M (2005) Control of dendritic arborization by the phosphoinositide-3鈥?kinase鈥揂kt鈥搈ammalian target of rapamycin pathway. J Neurosci 25:11300鈥?1312 CrossRef
  46. Santos AR, Comprido D, Duarte CB (2010) Regulation of local translation at the synapse by BDNF. Prog Neurobiol 92:505鈥?16 CrossRef
  47. Santini E, Klann E (2011) Dysregulated mTORC1-dependent translational control: From brain disorders to psychoactive drugs. Front Behav Neurosci 5:76 CrossRef
  48. Neves-Pereira M, M眉ller B, Massie D, Williams JH, O鈥橞rien PC, Hughes A et al (2009) Deregulation of EIF4E: A novel mechanism for autism. J Med Genet 46:759鈥?65 mg.2009.066852" target="_blank" title="It opens in new window">CrossRef
  49. Ahn Y, Narous M, Tobias R, Hu B, Rho JM (2012) Alterations in social behavior and mTOR signaling in the valproic acid-induced model of autism spectrum disorder, Program No. 861.21. 2012 Neuroscience Meeting Planner. Society for Neuroscience, New Orleans, LA, Online
  50. Williams RS, Hauser SL, Purpura DP, DeLong GR, Swisher CN (1980) Autism and mental retardation: neuropathologic studies performed in four retarded persons with autistic behavior. Arch Neurol 37:749鈥?53 CrossRef
  51. Correia CT, Coutinho AM, Sequeira AF, Sousa IG, Louren莽o Venda L, Almeida JP et al (2010) Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism. Genes Brain Behav 9:841鈥?48 CrossRef
  52. Weickert CS, Ligons DL, Romanczyk T, Ungaro G, Hyde TM, Herman MM et al (2005) Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia. Mol Psychiatry 10:637鈥?50 mp.4001678" target="_blank" title="It opens in new window">CrossRef
  53. Pillai A, Mahadik SP (2008) Increased truncated TrkB receptor expression and decreased BDNF/TrkB signaling in the frontal cortex of reeler mouse model of schizophrenia. Schizophr Res 100:325鈥?33 CrossRef
  54. Waterhouse EG, Xu B (2009) New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci 42:81鈥?9 mcn.2009.06.009" target="_blank" title="It opens in new window">CrossRef
  55. Klein R, Conway D, Parada LF, Barbacid M (1990) The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 61:647鈥?56 CrossRef
  56. Wong J, Rothmond DA, Webster MJ, Weickert C (2013) Increases in two truncated TrkB isoforms in the prefrontal cortex of people with schizophrenia. Schizophr Bull 39:130鈥?40 CrossRef
  57. Eide FF, Vining ER, Eide BL, Zang K, Wang XY, Reichardt LF (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 16:3123鈥?129
  58. Haapasalo A, Koponen E, Hoppe E, Wong G, Castr茅n E (2001) Truncated trkB.T1 is dominant negative inhibitor of trkB.TK鈥?鈥夆垝mediated cell survival. Biochem Biophys Res Commun 280:1352鈥?358 CrossRef
  59. Stoilov P, Castren E, Stamm S (2002) Analysis of the human TrkB gene genomic organization reveals novel TrkB isoforms, unusual gene length, and splicing mechanism. Biochem Biophys Res Commun 290:1054鈥?065 CrossRef
  60. Klein R, Parada LF, Coulier F, Barbacid M (1989) TrkB, a novel tyrosine protein kinase receptor expressed during mouse neural development. EMBO J 8:3701鈥?709
  61. Klein R, Nanduri V, Jing SA, Lamballe F, Tapley P, Bryant S et al (1991) The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 66:395鈥?03 CrossRef
  62. Rose CR, Blum R, Pichler B, Lepier A, Kafitz KW, Konnerth A (2003) Truncated TrkB-T1 mediates neurotrophin-evoked calcium signaling in glia cells. Nature 426:74鈥?8 CrossRef
  63. Romanczyk TB, Weickert CS, Webster MJ, Herman MM, Akil M, Kleinman JE (2002) Alterations in trkB mRNA in the human prefrontal cortex throughout the lifespan. Eur J Neurosci 15:269鈥?80 CrossRef
  64. Ohira K, Hayashi M (2003) Expression of TrkB subtypes in the adult monkey cerebellar cortex. J Chem Neuroanat 25:175鈥?83 CrossRef
  
• 作者单位：Chiara Nicolini (1)
  Younghee Ahn (2)
  Bernadeta Michalski (1)
  Jong M Rho (2)
  Margaret Fahnestock (1)
  
  1. Department of Psychiatry & Behavioural Neurosciences, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada
  2. Departments of Paediatrics & Clinical Neurosciences, Alberta Children鈥檚 Hospital Research Institute, University of Calgary, Calgary, AB, T3B 6A8, Canada
  
• 刊物主题：Neurosciences;
• 出版者：BioMed Central
• ISSN：2051-5960

文摘

Background The molecular mechanisms underlying autistic behaviors remain to be elucidated. Mutations in genes linked to autism adversely affect molecules regulating dendritic spine formation, function and plasticity, and some increase the mammalian target of rapamycin, mTOR, a regulator of protein synthesis at spines. Here, we investigated whether the Akt/mTOR pathway is disrupted in idiopathic autism and in rats exposed to valproic acid, an animal model exhibiting autistic-like behavior. Methods Components of the mTOR pathway were assayed by Western blotting in postmortem fusiform gyrus samples from 11 subjects with idiopathic autism and 13 controls and in valproic acid versus saline-exposed rat neocortex. Additionally, protein levels of brain-derived neurotrophic factor receptor (TrkB) isoforms and the postsynaptic organizing molecule PSD-95 were measured in autistic versus control subjects. Results Full-length TrkB, PI3K, Akt, phosphorylated and total mTOR, p70S6 kinase, eIF4B and PSD-95 were reduced in autistic versus control fusiform gyrus. Similarly, phosphorylated and total Akt, mTOR and 4E-BP1 and phosphorylated S6 protein were decreased in valproic acid- versus saline-exposed rats. However, no changes in 4E-BP1 or eIF4E were found in autistic brains. Conclusions In contrast to some monogenic disorders with high rates of autism, our data demonstrate down-regulation of the Akt/mTOR pathway, specifically via p70S6K/eIF4B, in idiopathic autism. These findings suggest that disruption of this pathway in either direction is widespread in autism and can have adverse consequences for synaptic function. The use of valproic acid, a histone deacetylase inhibitor, in rats successfully modeled these changes, implicating an epigenetic mechanism in these pathway disruptions.