title: Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid.
abstract: 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.
authors: Chiara
authors: C
authors: Nicolini
authors: Younghee
authors: Y
authors: Ahn
authors: Bernadeta
authors: B
authors: Michalski
authors: Jong M
authors: JM
authors: Rho
authors: Department of Psychiatry & Behavioural Neurosciences, McMaster University, 1280 Main Street West, Hamilton L8S 4K1, ON, Canada. fahnest@mcmaster.ca.
authors: Margaret
authors: M
authors: Fahnestock
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001321:Autistic Disorder / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D011180:Postmortem Changes; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013702:Temporal Lobe / Q000378:metabolism*; D014635:Valproic Acid / Q000633:toxicity*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D014635:Valproic Acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
references: Eur J Neurosci. 2002 Jan;15(2):269-80
references: 11849294
references: Mol Cell Neurosci. 2009 Oct;42(2):81-9
references: 19577647
references: Dev Neurobiol. 2010 Apr;70(5):304-22
references: 20186705
references: J Med Genet. 2009 Nov;46(11):759-65
references: 19556253
references: Neuropsychopharmacology. 2005 Jan;30(1):80-9
references: 15238991
references: Curr Opin Neurobiol. 2009 Apr;19(2):231-4
references: 19545994
references: Curr Biol. 1997 Sep 1;7(9):645-51
references: 9285718
references: J Neuropathol Exp Neurol. 2012 Apr;71(4):289-97
references: 22437340
references: Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R138-50
references: 16987877
references: Encephale. 1975;1(1):25-31
references: 1132367
references: Genes Dev. 2004 Aug 15;18(16):1926-45
references: 15314020
references: Cell. 2008 Oct 31;135(3):401-6
references: 18984149
references: J Chem Neuroanat. 2003 Mar;25(3):175-83
references: 12706205
references: Neuroscience. 2009 Nov 10;163(4):1201-10
references: 19607885
references: Neuroscience. 2010 Oct 13;170(2):514-22
references: 20603192
references: Schizophr Res. 2008 Mar;100(1-3):325-33
references: 18187310
references: Neuropsychopharmacology. 2008 Mar;33(4):901-12
references: 17507914
references: J Clin Invest. 2009 Apr;119(4):747-54
references: 19339766
references: EMBO J. 2013 Jun 12;32(12):1730-44
references: 23685357
references: CNS Drugs. 2002;16(10):669-94
references: 12269861
references: Mol Autism. 2011 May 06;2:6
references: 21548960
references: J Med Genet. 2000 Jul;37(7):489-97
references: 10882750
references: BMC Neurosci. 2010;11:102
references: 20723245
references: Reprod Toxicol. 1997 Mar-Jun;11(2-3):417-22
references: 9100317
references: Cereb Cortex. 2008 Apr;18(4):763-70
references: 17638926
references: Nature. 2003 Nov 6;426(6962):74-8
references: 14603320
references: Cold Spring Harb Perspect Biol. 2012 Mar;4(3). pii: a009886. doi: 10.1101/cshperspect.a009886
references: 22258914
references: Trends Mol Med. 2011 Feb;17(2):78-87
references: 21115397
references: Mol Psychiatry. 2014 Apr;19(4):495-503
references: 23608919
references: Prog Neurobiol. 2010 Dec;92(4):505-16
references: 20713125
references: Hum Mol Genet. 2011 Mar 15;20(6):1182-96
references: 21212100
references: Behav Brain Res. 2007 Jan 10;176(1):133-40
references: 17137645
references: EMBO J. 1989 Dec 1;8(12):3701-9
references: 2555172
references: J Autism Dev Disord. 1994 Oct;24(5):659-85
references: 7814313
references: Arch Psychiatr Nervenkr (1970). 1980;229(1):1-16
references: 6778456
references: Trends Neurosci. 2010 Feb;33(2):67-75
references: 19963289
references: Prog Neurobiol. 2012 Feb;96(2):268-82
references: 22285767
references: Mol Psychiatry. 2005 Jul;10(7):637-50
references: 15940304
references: Nature. 2013 Jan 17;493(7432):371-7
references: 23172145
references: J Child Psychol Psychiatry. 1992 Jul;33(5):843-59
references: 1634592
references: Front Neurosci. 2007 Oct 15;1(1):77-96
references: 18982120
references: Arch Neurol. 1980 Dec;37(12):749-53
references: 7447762
references: Cell. 1990 May 18;61(4):647-56
references: 2160854
references: J Neurosci. 1996 May 15;16(10):3123-9
references: 8627351
references: J Neurosci. 2005 Dec 7;25(49):11300-12
references: 16339025
references: J Neurochem. 1986 Dec;47(6):1713-9
references: 3772373
references: J Neurophysiol. 1994 Feb;71(2):821-5
references: 8176446
references: J Neurosci Res. 2010 Sep;88(12):2641-7
references: 20648653
references: Neurotoxicol Teratol. 2000 May-Jun;22(3):319-24
references: 10840175
references: Biochem Biophys Res Commun. 2002 Jan 25;290(3):1054-65
references: 11798182
references: Brain Res. 2010 Jan 14;1309:83-94
references: 19896929
references: Dev Med Child Neurol. 1994 Apr;36(4):361-9
references: 7512516
references: Biochem Biophys Res Commun. 2001 Feb 9;280(5):1352-8
references: 11162678
references: JAMA. 2013 Apr 24;309(16):1696-703
references: 23613074
references: Schizophr Bull. 2013 Jan;39(1):130-40
references: 21795612
references: Pediatr Res. 2002 Oct;52(4):576-9
references: 12357053
references: Int J Neuropsychopharmacol. 2013 Feb;16(1):91-103
references: 22093185
references: Front Behav Neurosci. 2011 Nov 08;5:76
references: 22073033
references: Arch Gen Psychiatry. 2000 Apr;57(4):331-40
references: 10768694
references: Front Neural Circuits. 2008 Oct 29;2:4
references: 18989389
references: Cell. 1991 Jul 26;66(2):395-403
references: 1649702
references: Genes Brain Behav. 2010 Oct;9(7):841-8
references: 20662941