Abstract
Dopamine plays a critical role in regulating neural activity in prefrontal cortex (PFC) and modulates cognition via a hypothesized inverse U function. We investigated PFC function in children with chromosome 22q11.2 deletion syndrome (22q11.2DS) in which one copy of catechol-O-methyltransferase (COMT) is deleted, thereby shifting them toward the lower end of dopamine turnover on the nonlinear function. A common polymorphism with valine to methionine substitution alters COMT activity that results in higher enzyme activity in the valine variant. Twenty-seven children with 22q11.2DS between 7 and 14 years old, and 21 age-matched typically developing children, performed a modified version of the Attention Network Test. Children with a single valine allele showed a reduction in response times when trials with incongruent flankers were repeated, whereas those who were hemizygous for the methionine allele did not show the same context-based response facilitation. Our results support that a single gene, COMT, could modulate PFC-dependent cognition.
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Baker, K., Baldeweg, T., Sivagnanasundaram, S., Scambler, P., & Skuse, D. (2005). COMT Val108/158Met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome. Biological Psychiatry, 58, 23–31.
Barnett, J. H., Jones, P. B., Robbins, T. W., & Müller, U. (2007). Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: A meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Molecular Psychiatry, 12, 502–509.
Bearden, C. E., Jawad, A. F., Lynch, D. R., Sokol, S., Kanes, S. J., McDonald-McGinn, D. M., et al. (2004). Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. American Journal of Psychiatry, 161, 1700–1702.
Bertolino, A., Blasi, G., Latorre, V., Rubino, V., Rampino, A., Sinibaldi, L., et al. (2006). Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain. Journal of Neuroscience, 26, 3918–3922.
Bish, J. P., Ferrante, S. M., McDonald-McGinn, D., Zackai, E., & Simon, T. J. (2005). Maladaptive conflict monitoring as evidence for executive dysfunction in children with chromosome 22q11.2 deletion syndrome. Developmental Science, 8, 36–43.
Blasi, G., Mattay, V. S., Bertolino, A., Elvevåg, B., Callicott, J. H., Das, S., et al. (2005). Effect of catechol-O-methyltransferase val158met genotype on attentional control. Journal of Neuroscience, 25, 5038–5045.
Boot, E., Booij, J., Zinkstok, J., Abeling, N., de Haan, L., Baas, F., et al. (2008). Disrupted dopaminergic neurotransmission in 22q11 deletion syndrome. Neuropsychopharmacology, 33, 1252–1258.
Botvinick, M. M., Cohen, J. D., & Carter, C. S. (2004). Conflict monitoring and anterior cingulate cortex: An update. Trends in Cognitive Sciences, 8, 539–546.
Bunge, S. A., Dudukovic, N. M., Thomason, M. E., Vaidya, C. J., & Gabrieli, J. D. E. (2002). Immature frontal lobe contributions to cognitive control in children: Evidence from fMRI. Neuron, 33, 301–311.
Chen, J., Lipska, B. K., Halim, N., Ma, Q. D., Matsumoto, M., Melhem, S., et al. (2004). Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain. American Journal of Human Genetics, 75, 807–821.
Debbane, M., Schaer, M., Farhoumand, R., Glaser, B., & Eliez, S. (2006). Hippocampal volume reduction in 22q11.2 deletion syndrome. Neuropsychologia, 44, 2360–2365.
Diamond, A., Briand, L., Fossella, J., & Gehlbach, L. (2004). Genetic and neurochemical modulation of prefrontal cognitive functions in children. American Journal of Psychiatry, 161, 125–132.
Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti, C. M., Straub, R. E., et al. (2001). Effect of COMT Val108/158Met genotype on frontal lobe function and risk for schizophrenia. Proceedings of the National Academy of Sciences, 98, 6917–6922.
Eliez, S., Blasey, C. M., Schmitt, E. J., White, C. D., Hu, D., & Reiss, A. L. (2001). Velocardiofacial syndrome: Are structural changes in the temporal and mesial temporal regions related to schizophrenia? American Journal of Psychiatry, 158, 447–453.
Fan, J., McCandliss, B. D., Sommer, T., Raz, A., & Posner, M. I. (2002). Testing the efficiency and independence of attentional networks. Journal of Cognitive Neuroscience, 14, 340–347.
Freund, T. F., Powell, J. F., & Smith, A. D. (1984). Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines. Neuroscience, 13, 1189–1215.
Glaser, B., Debbane, M., Hinard, C., Morris, M. A., Dahoun, S. P., Antonarakis, S. E., & Eliez, S. (2006). No evidence for an effect of COMT Val158Met genotype on executive function in patients with 22q11 deletion syndrome. American Journal of Psychiatry, 163, 537–539.
Gothelf, D., Eliez, S., Thompson, T., Hinard, C., Penniman, L., Feinstein, C., et al. (2005). COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nature Neuroscience, 8, 1500–1502.
Gothelf, D., Michaelovsky, E., Frisch, A., Zohar, A. H., Presburger, G., Burg, M., et al. (2007). Association of the low-activity COMT 158Met allele with ADHD and OCD in subjects with velocardiofacial syndrome. International Journal of Neuropsychopharmacology, 10, 301–308.
Grace, A. A., Floresco, S. B., Goto, Y., & Lodge, D. J. (2007). Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends in Neurosciences, 30, 220–227.
Gratton, G., Coles, M. G., & Donchin, E. (1992). Optimizing the use of information: Strategic control of activation of responses. Journal of Experimental Psychology: General, 121, 480–506.
Honey, G. D., Suckling, J., Zelaya, F., Long, C., Routledge, C., Jackson, S., et al. (2003). Dopaminergic drug effects on physiological connectivity in a human cortico-striato-thalamic system. Brain, 126, 1767–1781.
Karoum, F., Chrapusta, S. J., & Egan, M. F. (1994). 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: Reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. Journal of Neurochemistry, 63, 972–979.
Kates, W. R., Antshel, K. M., Abdulsabur, N., Colgan, D., Funke, B., Fremont, W., et al. (2006). A gender-moderated effect of a functional COMT polymorphism on prefrontal brain morphology and function in velo-cardio-facial syndrome (22q11.2 deletion syndrome). American Journal of Medical Genetics, 141B, 274–280.
Kimberg, D. Y., & D’Esposito, M. (2003). Cognitive effects of the dopamine receptor agonist pergolide. Neuropsychologia, 41, 1020–1027.
Kornhuber, J., & Kornhuber, M. E. (1983). Axo-axonic synapses in the rat striatum. European Neurology, 22, 433–436.
Maynard, T. M., Haskell, G. T., Lieberman, J. A., & LaMantia, A. S. (2002). 22q11 DS: Genomic mechanisms and gene function in DiGeorge/velocardiofacial syndrome. International Journal of Developmental Neuroscience, 20, 407–419.
Mayr, U., Awh, E., & Laurey, P. (2003). Conflict adaptation effects in the absence of executive control. Nature Neuroscience, 6, 450–452.
Murphy, K. C. (2002). Schizophrenia and velo-cardio-facial syndrome. Lancet, 359, 426–430.
Rosenberg, D. R., & Lewis, D. A. (1995). Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: A tyrosine hydroxylase immunohistochemical analysis. Journal of Comparative Neurology, 358, 383–400.
Seamans, J. K., & Yang, C. R. (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Progress in Neurobiology, 74, 1–58.
Shashi, V., Keshavan, M. S., Howard, T. D., Berry, M. N., Basehore, M. J., Lewandowski, E., et al. (2006). Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome. Clinical Genetics, 69, 234–238.
Simon, T. J., Bearden, C. E., McGinn, D. M., & Zackai, E. (2005). Visuospatial and numerical cognitive deficits in children with chromosome 22q11.2 deletion syndrome. Cortex, 41, 145–155.
Sobin, C., Kiley-Brabeck, K., & Karayiorgou, M. (2005). Lower prepulse inhibition in children with the 22q11 deletion syndrome. American Journal of Psychiatry, 162, 1090–1099.
Tunbridge, E. M., Weickert, C. S., Kleinman, J. E., Herman, M. M., Chen, J., Kolachana, B. S., et al. (2007). Catechol-o-methyltransferase enzyme activity and protein expression in human prefrontal cortex across the postnatal lifespan. Cerebral Cortex, 17, 1206–1212.
Wahlstrom, D., White, T., Hooper, C. J., Vrshek-Schallhorn, S., Oetting, W. S., Brott, M. J., & Luciana, M. (2007). Variations in the catechol O-methyltransferase polymorphism and prefrontally guided behaviors in adolescents. Biological Psychiatry, 61, 626–632.
Williams, G. V., & Goldman-Rakic, P. S. (1995). Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature, 376, 572–575.
Winterer, G., Musso, F., Vucurevic, G., Stoeter, P., Konrad, A., Seker, B., et al. (2006). COMT genotype predicts BOLD signal and noise characteristics in prefrontal circuits. NeuroImage, 32, 1722–1732.
Winterer, G., & Weinberger, D. R. (2004). Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends in Neurosciences, 27, 683–690.
Zavitsanou, K., Cranney, J., & Richardson, R. (1999). Dopamine antagonists in the orbital prefrontal cortex reduce prepulse inhibition of the acoustic startle reflex in the rat. Pharmacology, Biochemistry, & Behavior, 63, 55–61.
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Takarae, Y., Schmidt, L., Tassone, F. et al. Catechol-O-methyltransferase polymorphism modulates cognitive control in children with chromosome 22q11.2 deletion syndrome. Cognitive, Affective, & Behavioral Neuroscience 9, 83–90 (2009). https://doi.org/10.3758/CABN.9.1.83
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DOI: https://doi.org/10.3758/CABN.9.1.83