Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum

  1. Eric R. Kandel1,2,4,9,10
  1. 1Department of Psychiatry, Columbia University, New York, New York 10032, USA
  2. 2New York State Psychiatric Institute, New York, New York 10032, USA
  3. 3Department of Neuroscience and Physiology, University of Gothenburg, SE-405 30 Gothenburg, Sweden
  4. 4Department of Neuroscience, Columbia University, New York, New York 10032, USA
  5. 5Department of Neurosciences, Université Claude Bernard, 69372 Lyon, France
  6. 6Weill Cornell Medical College, New York, New York 10021, USA
  7. 7Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA
  8. 8Department of Pharmacology, Columbia University, New York, New York 10032, USA
  9. 9Howard Hughes Medical Institute, New York, New York 10032, USA
  10. 10Kavli Institute for Brain Science, Columbia University, New York, New York 10032, USA

    Abstract

    A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val158 allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans. Here we explore a novel transgenic mouse model of increased COMT activity, equivalent to the relative increase in activity observed with the human COMT Val158 allele. By performing an extensive battery of behavioral tests, we found that COMT overexpressing mice (COMT-OE mice) exhibit cognitive deficits selectively in the domains that are affected by the COMT Val158 allele, stimulus–response learning and working memory, functionally validating our model of increased COMT activity. Although we detected no changes in the level of markers for dopamine synthesis and dopamine transport, we found that COMT-OE mice display an increase in dopamine release capacity in the striatum. This result suggests that increased COMT activity may not only affect dopamine signaling by enhancing synaptic clearance in the cortex, but may also cause changes in presynaptic dopamine function in the striatum. These changes may underlie the behavioral deficits observed in the mice and might also play a role in the cognitive deficits and increased psychiatric disease risk associated with genetic variation in COMT activity in humans.

    Footnotes

    • 11 Corresponding author

      E-mail es534{at}columbia.edu

    • Received June 10, 2013.
    • Accepted February 3, 2014.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first 12 months after the full-issue publication date (see ). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at .

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