Abstract
Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Arnold H, Burk J, Hodgson E, Sarter M, Bruno J (2002). Differential cortical acetylcholine release in rats performing a sustained attention task versus behavioral control tasks that do not explicitly tax attention. Neuroscience 114: 451–460.
Association AP, DSM-IV (2000). APATF on (American Psychiatric Pub). Diagnostic and statistical manual of mental disorders: DSM-IV-TR.
Avale ME, Chabout J, Pons S, Serreau P, Chaumont FD, Olivo-Marin J-C et al (2011). Prefrontal nicotinic receptors control novel social interaction between mice. FASEB J 25: 2145–2155.
Bolivar VJ, Walters SR, Phoenix JL (2007). Assessing autism-like behavior in mice: variations in social interactions among inbred strains. Behav Brain Res 176: 21–26.
Buckley AW, Sassower K, Rodriguez AJ, Jennison K, Wingert K, Buckley J et al (2011). An open label trial of Donepezil for enhancement of rapid eye movement sleep in young children with autism spectrum disorders. J Child Adolescent Psychopharmacol 21: 353–357.
Canitano R, Scandurra V (2011). Psychopharmacology in autism: an update. Progress Neuro-Psychopharmacol Biol Psychiatry 35: 18–28.
Chadman KK, Guariglia SR (2012). The BTBR T+tf/J (BTBR) mouse model of autism. Autism S1: 009.
Chez M, Buchanan T, Becker M, Kessler J, Aimonovitch M, Mrazek S (2003). Donepezil hydrochloride: a double-blind study in autistic children. J Pediatric Neurol 1: 83–88.
Dam D, Van, Abramowski D, Staufenbiel M, De Deyn PP (2005). Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model. Psychopharmacol (Berl) 180: 177–190.
Deutsch SI, Urbano MR, Neumann SA, Burket JA, Katz E (2010). Cholinergic abnormalities in autism. Clinical Neuropharmacol 33: 114–120.
Dong H, Csernansky CA, Martin MV, Bertchume A, Vallera D, Csernansky JG (2005). Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease. Psychopharmacol (Berl) 181: 145–152.
Eggermann E, Feldmeyer D (2009). Cholinergic filtering in the recurrent excitatory microcircuit of cortical layer 4. PNAS 106: 11753–11758.
Ellegood J, Babineau BA, Henkelman RM, Lerch JP, Crawley JN (2013a). Neuroanatomical analysis of the BTBR mouse model of autism using magnetic resonance imaging and diffusion tensor imaging. NeuroImage 70: 288–300.
Ellegood J, Babineau BA, Henkelman RM, Lerch JP, Crawley JN (2013b). Neuroanatomical analysis of the BTBR mouse model of autism using magnetic resonance imaging and diffusion tensor imaging. NeuroImage 70: 288–300.
Franklin KBJ, Paxinos G (1997) The mouse brain atlas in stereotaxic coordinates. Academic Press: San Diego, CA, USA.
Friedman SDSD (2006). GRay and white matter brain chemistry in young children with autism. Arch Gen Psychiatry 63: 786–794.
Gao S, Singer HS (2013). Complex motor stereotypies: an evolving neurobiological concept. Future Neurology 8: 273–285.
Goldberg JA, Reynolds JNJ (2011). Spontaneous firing and evoked pauses in the tonically active cholinergic interneurons of the striatum. Neuroscience 198: 27–43.
Grahn JA, Parkinson JA, Owen AM (2008). The cognitive functions of the caudate nucleus. Progress Neurobiol 86: 141–155.
Granon S, Faure P, Changeux J-P (2003). Executive and social behaviors under nicotinic receptor regulation. PNAS 100: 9596–9601.
Graybiel AM, Aosaki T, Flaherty AW, Kimura M (1994). The basal ganglia and adaptive motor control. Science 265: 1826–1831.
Guariglia SR, Jenkins EC Jr., Chadman KK, Wen GY (2011). Chlorination byproducts induce gender specific autistic-like behaviors in CD-1 mice. NeuroToxicol 32: 545–553.
Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T et al (2011). Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68: 1095–1102.
Handen BL, Johnson CR, McAuliffe-Bellin S, Murray PJ, Hardan AY (2011). Safety and efficacy of Donepezil in children and adolescents with autism: neuropsychological measures. J Child Adolescent Psychopharmacol 21: 43–50.
Hardan AY, Handen BL (2002). A retrospective open trial of adjunctive donepezil in children and adolescents with autistic disorder. J Child Adolesc Psychopharmacol 12: 237–241.
Karvat G, Kimchi T (2012). Systematic autistic-like behavioral phenotyping of 4 mouse strains using a novel wheel-running assay. Behav Brain Res 233: 405–414.
Kemp J, Berthel M-C, Dufour A, Després O, Henry A, Namer IJ et al (2013). Caudate nucleus and social cognition: neuropsychological and SPECT evidence from a patient with focal caudate lesion. Cortex 49: 559–571.
Kemper TL, Bauman M (1998). Neuropathology of infantile Autism. J Neuropathol Experimental Neurol 57: 645–652.
Klin A, Danovitch JH, Merz AB, Volkmar FR (2007). Circumscribed interests in higher functioning individuals with autism spectrum disorders: an exploratory study. Res Practice Persons with Severe Disabilities 32: 89–100.
Lauder JM, Schambra UB (1999). Morphogenetic roles of acetylcholine. Environ Health Perspect 107: 65–69.
Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G et al (2012). Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism Spectrum disorders. PLoS Genet 8: e1002521.
McConville BJ, Sanberg PR, Fogelson MH, King J, Cirino P, Parker KW et al (1992). The effects of nicotine plus haloperidol compared to nicotine only and placebo nicotine only in reducing tic severity and frequency in Tourette’s disorder. Biol Psychiatry 31: 832–840.
McCool MF, Patel S, Talati R, Ragozzino ME (2008). Differential involvement of M1-type and M4-type muscarinic cholinergic receptors in the dorsomedial striatum in task switching. Neurobiol Learn Mem 89: 114–124.
McTighe SM, Neal SJ, Lin Q, Hughes ZA, Smith DG (2013). The BTBR mouse model of autism spectrum disorders has learning and attentional impairments and alterations in acetylcholine and kynurenic acid in prefrontal cortex. PLoS One 8: e62189.
Mesulam M-M, Mufson EJ, Wainer BH, Levey AI (1983). Central cholinergic pathways in the rat: An overview based on an alternative nomenclature (Ch1–Ch6). Neuroscience 10: 1185–1201.
Mikhail FM, Lose EJ, Robin NH, Descartes MD, Rutledge KD, Rutledge SL et al (2011). Clinically relevant single gene or intragenic deletions encompassing critical neurodevelopmental genes in patients with developmental delay, mental retardation, and/or autism spectrum disorders. AmJ Medical Genet Part A 155: 2386–2396.
Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP et al (2007). Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 176: 4–20.
Mukaetova-Ladinska EB, Westwood J, Perry EK (2010). Cholinergic component of autism spectrum disorder. The Neurochemical Basis of Autism 129–161.
Pepeu G, Giovannini MG (2004). Changes in acetylcholine extracellular levels during cognitive processes. Learn Mem 11: 21–27.
Ragozzino ME, Choi D (2004). Dynamic changes in acetylcholine output in the medial striatum during place reversal learning. Learn Mem 11: 70–77.
Ragozzino ME, Pal SN, Unick K, Stefani MR, Gold PE (1998). Modulation of hippocampal acetylcholine release and spontaneous alternation scores by intrahippocampal glucose injections. J Neurosci 18: 1595–1601.
Riedel G, Kang SH, Choi DY, Platt B (2009). Scopolamine-induced deficits in social memory in mice: reversal by donepezil. Behav Brain Res 204: 217–225.
Rubenstein JLR, Merzenich MM (2003). Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes, Brain Behav 2: 255–267.
Sears LL, Vest C, Mohamed S, Bailey J, Ranson BJ, Piven J (1999). An MRI study of the basal ganglia in autism. Prog Neuro-Psychopharmacol Biol Psychiatry 23: 613–624.
Silverman JL, Smith DG, Rizzo SJS, Karras MN, Turner SM, Tolu SS et al (2012). Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci Transl Med 4: 131ra51–131ra51.
Sokol DK, Dunn DW, Edwards-Brown M, Feinberg J (2002). Hydrogen proton magnetic resonance spectroscopy in autism: preliminary evidence of elevated choline/creatine ratio. J Child Neurol 17: 245–249.
Spowart-Manning L, van der Staay F (2004). The T-maze continuous alternation task for assessing the effects of putative cognition enhancers in the mouse. Behav Brain Res 151: 37–46.
Srivastava RK, Agarwal M, Pundhir A (2011). Role of Donepezil in autism: its conduciveness in psychopharmacotherapy. Case Rep Psychiatry 2011: 1–2.
Turner-Brown LM, Lam KSL, Holtzclaw TN, Dichter GS, Bodfish JW (2011). Phenomenology and measurement of circumscribed interests in autism spectrum disorders. Autism 15: 437–456.
Walker BR, Diefenbach KS, Parikh TN (2007). Inhibition within the nucleus tractus solitarius (NTS) ameliorates environmental exploration deficits due to cerebellum lesions in an animal model for autism. Behav Brain Res 176: 109–120.
Wang H, Tang XC (1998). Anticholinesterase effects of huperzine A, E2020, and tacrine in rats. Zhongguo Yao Li Xue Bao 19: 27–30.
Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ et al (2011). Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477: 171–178.
Yoo JH, Valdovinos MG, Williams DC (2007). Relevance of Donepezil in enhancing learning and memory in special populations: a review of the literature. J Autism Dev Disord 37: 1883–1901.
Acknowledgements
We thank M Dayan, L Edry, Y Sofer, N Barak, and L Khalfin for their assistance in conducting the experiments. We also thank A Weissbrod for his assistance with designing and building the experimental set-up.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Neuropsychopharmacology website
Supplementary information
Rights and permissions
About this article
Cite this article
Karvat, G., Kimchi, T. Acetylcholine Elevation Relieves Cognitive Rigidity and Social Deficiency in a Mouse Model of Autism. Neuropsychopharmacol 39, 831–840 (2014). https://doi.org/10.1038/npp.2013.274
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2013.274
Keywords
This article is cited by
-
Exploring the impact of acute physical activity on creative thinking: a comprehensive narrative review with a focus on activity type and intensity
Discover Psychology (2024)
-
Maturation of nucleus accumbens synaptic transmission signals a critical period for the rescue of social deficits in a mouse model of autism spectrum disorder
Molecular Brain (2023)
-
Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency: Role of prefrontal cortex projections in cognitive deficits
Translational Psychiatry (2023)
-
Acetylcholine modulates the temporal dynamics of human theta oscillations during memory
Nature Communications (2023)
-
Neuroprotective Efficacy of Fisetin Against VPA-Induced Autistic Neurobehavioral Alterations by Targeting Dysregulated Redox Homeostasis
Journal of Molecular Neuroscience (2023)
