title: Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression.
abstract: BACKGROUND
  A number of studies have associated reduced Akt1 expression with vulnerability for schizophrenia. Although mice with deletion of a single copy of the Akt1 gene (Akt1(+/-)) show reduced Akt1 expression relative to wild-type (WT) animals, the extent to which these mice show schizophrenia-like phenotypic changes and/or increased susceptibility to epigenetic or non-genetic factors related to schizophrenia is unknown.
  
  
  OBJECTIVE
  Mutant mice were assessed on electroencephalographic/event-related potential (EEG/ERP) and behavioral (acoustic startle and pre-pulse inhibition) measures relevant to schizophrenia. Mice were also assessed following exposure to the NMDA receptor antagonist ketamine, a potent psychotomimetic drug, in order to assess the role of reduced Akt1 expression as a vulnerability factor for schizophrenia. Methods Akt1(+/-), Akt1(-/-), and WT mice received a series of paired-click, white noise stimuli, following ketamine (50 mg/kg) and saline injections. EEG was analyzed for ERPs and event-related power. Akt1(+/-) and WT mice were also assessed on PPI following ketamine (50 mg/kg) or saline injection.
  
  
  RESULTS
  Akt1(+/-) and Akt1(-/-) mice displayed reduced amplitude of the P20 component of the ERP to the first click of a paired-click stimulus, as well as reduced S1-S2 difference for P20 and N40 components, following ketamine. Mutant mice also showed increased reduction in gamma synchrony and theta suppression following ketamine. Akt1(+/-) mice displayed reduced pre-pulse inhibition.
  
  
  CONCLUSIONS
  Reduced genetic expression of Akt1 facilitated ketamine-induced changes of EEG and behavior in mice, suggesting that reduced Akt1 expression can serve as a vulnerability factor for schizophrenia.
authors: Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pennsylvania, 125 South 31st Street, Philadelphia, PA 19104, USA. refeatherstone@gmail.com
authors: Robert E
authors: RE
authors: Featherstone
authors: Valerie
authors: V
authors: M Tatard-Leitman
authors: Jimmy D
authors: JD
authors: Suh
authors: Robert
authors: R
authors: Lin
authors: Irwin
authors: I
authors: Lucki
authors: Steven J
authors: SJ
authors: Siegel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004569:Electroencephalography; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*; D013826:Theta Rhythm
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
references: Biol Psychiatry. 2002 Nov 1;52(9):887-95
references: 12399142
references: Neuroscience. 2007 Feb 23;144(4):1314-23
references: 17184927
references: Schizophr Bull. 2006 Oct;32(4):692-700
references: 16469942
references: Electroencephalogr Clin Neurophysiol. 1993 Apr;86(4):283-93
references: 7682932
references: Neuroscience. 2004;129(1):101-7
references: 15489033
references: Mol Psychiatry. 2012 Oct;17(10):1007-16
references: 21788944
references: Neuropsychopharmacology. 1999 Feb;20(2):106-18
references: 9885791
references: Neuropsychopharmacology. 1996 May;14(5):301-7
references: 8703299
references: Brain Res Brain Res Rev. 1999 Apr;29(2-3):169-95
references: 10209231
references: Biol Psychiatry. 1999 Oct 1;46(7):990-6
references: 10509182
references: Biol Psychiatry. 2012 May 15;71(10):873-80
references: 22361076
references: Nat Genet. 2004 Feb;36(2):131-7
references: 14745448
references: Arch Gen Psychiatry. 1992 Mar;49(3):206-15
references: 1567275
references: Psychiatry Res. 2004 May 30;126(3):203-15
references: 15157747
references: Mol Psychiatry. 2012 May;17(5):537-48
references: 21468034
references: Biol Psychiatry. 2012 Nov 15;72(10):811-6
references: 22831980
references: Neuropsychopharmacology. 1997 Sep;17(3):141-50
references: 9272481
references: Arch Gen Psychiatry. 1999 Nov;56(11):1001-5
references: 10565499
references: Neuropsychopharmacology. 2011 Nov;36(12):2529-37
references: 21775978
references: Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1158-63
references: 21187413
references: J Psychiatr Res. 2012 Mar;46(3):279-84
references: 22209534
references: J Clin Invest. 2008 Jun;118(6):2200-8
references: 18497887
references: Behav Neurosci. 2012 Apr;126(2):332-43
references: 22309446
references: Pharmacol Ther. 2010 Dec;128(3):419-32
references: 20705091
references: Neuropsychopharmacology. 1995 Aug;13(1):9-19
references: 8526975
references: Genes Brain Behav. 2012 Mar;11(2):157-69
references: 22151747
references: Biol Psychiatry. 1983 May;18(5):537-51
references: 6134559
references: Schizophr Res. 2009 Sep;113(2-3):339-46
references: 19524407
references: Psychopharmacology (Berl). 1999 Feb;142(1):9-17
references: 10102777
references: Science. 2007 Dec 7;318(5856):1645-7
references: 18063801
references: Neuroscience. 2009 Jan 23;158(2):705-12
references: 19015010
references: Am J Psychiatry. 2010 Oct;167(10):1264-75
references: 20634366
references: Psychopharmacology (Berl). 1995 May;119(2):163-70
references: 7659763
references: J Neurosci. 1997 Apr 15;17(8):2921-7
references: 9092613
references: Schizophr Res. 2009 Sep;113(2-3):332-8
references: 19628376
references: Neuropsychopharmacology. 2003 Apr;28(4):675-82
references: 12655312
references: Neurochem Res. 2004 Jun;29(6):1179-88
references: 15176475
references: J Cogn Neurosci. 2010 Jul;22(7):1452-64
references: 19583475
references: Schizophr Res. 1998 Oct 9;33(3):157-67
references: 9789908
references: Neurobiol Dis. 2012 Sep;47(3):338-46
references: 22627142
references: Brain Res. 2008 Oct 15;1235:133-42
references: 18621027
references: Psychophysiology. 2009 Sep;46(5):1059-68
references: 19515106
references: J Psychiatr Res. 1999 Nov-Dec;33(6):523-33
references: 10628529
references: Mol Cell Biol. 2012 Jan;32(1):96-106
references: 22037765
references: J Cogn Neurosci. 2008 Aug;20(8):1403-14
references: 18303985
references: World J Biol Psychiatry. 2013 Mar;14(2):100-13
references: 22150081
references: Neuropsychopharmacology. 2001 Oct;25(4):455-67
references: 11557159
references: Psychopharmacology (Berl). 1998 Jun;137(3):271-81
references: 9683005
references: Neuroscience. 2005;133(3):729-38
references: 15908134
references: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16906-11
references: 17077150
references: Neuropsychopharmacology. 2004 Apr;29(4):739-46
references: 14735128
references: Schizophr Bull. 2008 Sep;34(5):907-26
references: 18684772
references: J Abnorm Psychol. 2008 Feb;117(1):106-18
references: 18266489
references: J Biol Chem. 2001 Oct 19;276(42):38349-52
references: 11533044
references: Arch Gen Psychiatry. 1994 Mar;51(3):199-214
references: 8122957
references: J Pharmacol Exp Ther. 2006 Jan;316(1):315-24
references: 16192313
references: Schizophr Res. 2004 Oct 1;70(2-3):303-13
references: 15329306
references: Psychopharmacology (Berl). 2009 Mar;202(4):745-51
references: 18931833
references: Schizophr Bull. 1998;24(2):189-202
references: 9613620
references: Psychophysiology. 2009 May;46(3):566-77
references: 19298628
references: Hippocampus. 2012 Feb;22(2):230-40
references: 21049487
references: Psychiatry Res. 2009 Jan 30;165(1-2):27-37
references: 18990453
references: J Neurosci Methods. 2004 Mar 15;134(1):9-21
references: 15102499