title: The BTBR mouse model of autism spectrum disorders has learning and attentional impairments and alterations in acetylcholine and kynurenic acid in prefrontal cortex.
abstract: Autism is a complex spectrum of disorders characterized by core behavioral deficits in social interaction, communication, repetitive stereotyped behaviors and restricted interests. Autism frequently presents with additional cognitive symptoms, including attentional deficits and intellectual disability. Preclinical models are important tools for studying the behavioral domains and biological underpinnings of autism, and potential treatment targets. The inbred BTBR T+tf/J (BTBR) mouse strain has been used as an animal model of core behavioral deficits in autism. BTBR mice exhibit repetitive behaviors and deficits in sociability and communication, but other aspects of their cognitive phenotype, including attentional performance, are not well characterized. We examined the attentional abilities of BTBR mice in the 5-choice serial reaction time task (5-CSRTT) using an automated touchscreen testing apparatus. The 5-CSRTT is an analogue of the human continuous performance task of attention, and so both the task and apparatus have translational relevance to human touchscreen cognitive testing. We also measured basal extracellular levels of a panel of neurotransmitters within the medial prefrontal cortex, a brain region critically important for performing the 5-CSRTT. We found that BTBR mice have increased impulsivity, defined as an inability to withhold responding, and decreased motivation, as compared to C57Bl/6J mice. Both of these features characterize attentional deficit disorders in humans. BTBR mice also display decreased accuracy in detecting short stimuli, lower basal levels of extracellular acetylcholine and higher levels of kynurenic acid within the prefrontal cortex. Intact cholinergic transmission in prefrontal cortex is required for accurate performance of the 5-CSRTT, consequently this cholinergic deficit may underlie less accurate performance in BTBR mice. Based on our findings that BTBR mice have attentional impairments and alterations in a key neural substrate of attention, we propose that they may be valuable for studying mechanisms for treatment of cognitive dysfunction in individuals with attention deficits and autism.
authors: Neuroscience Research Unit, Pfizer Global Research and Development, Cambridge, Massachusetts, United States of America. Stephanie.McTighe@pfizer.com
authors: Stephanie M
authors: SM
authors: McTighe
authors: Sarah J
authors: SJ
authors: Neal
authors: Qian
authors: Q
authors: Lin
authors: Zoë A
authors: ZA
authors: Hughes
authors: Daniel G
authors: DG
authors: Smith
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001288:Attention; D002659:Child Development Disorders, Pervasive / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D006120:Grooming; D006801:Humans; D007736:Kynurenic Acid / Q000378:metabolism*; D007858:Learning; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018377:Neurotransmitter Agents / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000503:physiopathology*; D011597:Psychomotor Performance; D011930:Reaction Time
chemical_list: D018377:Neurotransmitter Agents; D007736:Kynurenic Acid; D000109:Acetylcholine
references: Behav Brain Res. 1983 Sep;9(3):361-80
references: 6639741
references: Psychopharmacology (Berl). 2002 Oct;163(3-4):362-80
references: 12373437
references: Eur J Neurosci. 2000 Aug;12(8):3051-8
references: 10971646
references: J Neurosci. 1994 Apr;14(4):2313-26
references: 7512637
references: Behav Brain Res. 2007 Jan 10;176(1):4-20
references: 16971002
references: Science. 2007 Mar 2;315(5816):1267-70
references: 17332411
references: Expert Rev Neurother. 2008 Apr;8(4):657-69
references: 18416666
references: Neuropharmacology. 2000 Aug 23;39(11):2170-9
references: 10963760
references: Curr Psychiatry Rep. 2010 Oct;12(5):382-8
references: 20694583
references: Behav Brain Res. 2010 Dec 25;214(2):443-9
references: 20600340
references: Behav Res Methods. 2010 Nov;42(4):1059-71
references: 21139173
references: Genes Brain Behav. 2011 Mar;10(2):228-35
references: 21040460
references: Behav Brain Res. 2012 Sep 1;234(1):33-7
references: 22677272
references: Learn Mem. 2008 Jul 08;15(7):516-23
references: 18612068
references: Nat Protoc. 2008;3(5):759-67
references: 18451784
references: Ann N Y Acad Sci. 1998 Jun 21;846:222-37
references: 9668410
references: Neuropsychopharmacology. 2010 Mar;35(4):976-89
references: 20032969
references: Genes Brain Behav. 2011 Feb;10(1):35-43
references: 20345893
references: Int J Dev Neurosci. 2007 Dec;25(8):515-21
references: 17980995
references: Learn Mem. 2004 Jan-Feb;11(1):78-86
references: 14747520
references: Psychol Med. 1999 Jul;29(4):769-86
references: 10473304
references: J Neurosci. 2011 Mar 2;31(9):3500-7
references: 21368062
references: Curr Neuropharmacol. 2011 Mar;9(1):209-14
references: 21886592
references: Res Dev Disabil. 2009 Jul-Aug;30(4):763-73
references: 19070990
references: JAMA. 2001 Jun 27;285(24):3093-9
references: 11427137
references: Genes Brain Behav. 2011 Feb;10(1):44-56
references: 20618443
references: Biol Psychiatry. 2001 Oct 1;50(7):521-30
references: 11600105
references: Br J Pharmacol. 2009 May;157(2):307-19
references: 19338583
references: MMWR Surveill Summ. 2012 Mar 30;61(3):1-19
references: 22456193
references: Mol Psychiatry. 2011 Nov;16(11):1147-54
references: 20856250
references: Cereb Cortex. 1996 May-Jun;6(3):470-81
references: 8670672
references: Science. 2012 Sep 14;337(6100):1301-3
references: 22984058
references: Neuron. 2011 Feb 24;69(4):680-94
references: 21338879
references: Physiol Behav. 2007 Sep 10;92(1-2):203-9
references: 17573079
references: Dementia. 1994 Sep-Oct;5(5):266-81
references: 7951684
references: Behav Brain Res. 2008 Mar 17;188(1):178-94
references: 18068825
references: Neuropharmacology. 2011 Dec;61(8):1366-78
references: 21903112
references: Nat Rev Neurosci. 2012 Jul;13(7):465-77
references: 22678511
references: Dev Neurorehabil. 2010;13(6):408-12
references: 21034283
references: Neuroscience. 2010 Dec 29;171(4):1197-208
references: 20888890
references: Schizophr Bull. 1987;13(4):669-78
references: 2894074
references: J Neurosci. 2002 Mar 1;22(5):1905-13
references: 11880520
references: Curr Protoc Neurosci. 2005 May;Chapter 8:Unit 8.5H
references: 18428627
references: Res Dev Disabil. 2010 May-Jun;31(3):743-9
references: 20206472
references: Front Behav Neurosci. 2007 Nov 02;1:1
references: 18958184
references: Brain Dev. 2009 Feb;31(2):95-103
references: 19006654
references: Sci Transl Med. 2011 Aug 10;3(95):95ra75
references: 21832240
references: Genetics. 2006 Aug;173(4):2407-10
references: 16751659
references: Behav Brain Res. 1989 Dec 1;35(3):221-40
references: 2688683
references: Am J Intellect Dev Disabil. 2012 Mar;117(2):103-20
references: 22515826
references: Behav Brain Res. 2012 Feb 1;227(1):64-72
references: 22056750
references: Sci Transl Med. 2012 Apr 25;4(131):131ra51
references: 22539775
references: Amino Acids. 2000;19(1):283-97
references: 11026500
references: Brain Res. 2011 Mar 22;1380:42-77
references: 21129364
references: Autism Res. 2011 Feb;4(1):5-16
references: 21328568
references: J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Jul 15;879(22):2023-33
references: 21684223
references: Autism Res. 2009 Dec;2(6):322-33
references: 19998356
references: Neuropsychopharmacology. 2008 May;33(6):1323-35
references: 17625499
references: Behav Neurosci. 2001 Aug;115(4):957-60
references: 11508736
references: PLoS One. 2008 Aug 27;3(8):e3067
references: 18728777
references: Genes Brain Behav. 2008 Mar;7(2):152-63
references: 17559418
references: Hum Mol Genet. 2000 May 22;9(9):1415-23
references: 10814723
references: Curr Neurol Neurosci Rep. 2011 Aug;11(4):428-34
references: 21424677
references: Neuron. 2007 Oct 4;56(1):141-54
references: 17920021
references: Physiol Behav. 2012 Dec 5;107(5):649-62
references: 22245067
references: Psychopharmacology (Berl). 2012 Jan;219(2):253-70
references: 22089700
references: Schizophr Res. 2005 Dec 15;80(2-3):315-22
references: 16125901