title: Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum.
abstract: A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val(158) 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 Val(158) 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 Val(158) 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.
authors.affiliation: Department of Psychiatry, Columbia University, New York, New York 10032, USA.
authors.forename: Eleanor H
authors.initials: EH
authors.lastname: Simpson
authors.forename: Julia
authors.initials: J
authors.lastname: Morud
authors.forename: Vanessa
authors.initials: V
authors.lastname: Winiger
authors.forename: Dominik
authors.initials: D
authors.lastname: Biezonski
authors.forename: Judy P
authors.initials: JP
authors.lastname: Zhu
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Bach
authors.forename: Gael
authors.initials: G
authors.lastname: Malleret
authors.forename: H Jonathan
authors.initials: HJ
authors.lastname: Polan
authors.forename: Scott
authors.initials: S
authors.lastname: Ng-Evans
authors.forename: Paul E M
authors.initials: PE
authors.lastname: Phillips
authors.forename: Christoph
authors.initials: C
authors.lastname: Kellendonk
authors.forename: Eric R
authors.initials: ER
authors.lastname: Kandel
mesh_terms: D000818:Animals; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D003071:Cognition / Q000502:physiology; D003192:Compulsive Behavior / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D007175:Impulsive Behavior; D007858:Learning / Q000502:physiology*; D007859:Learning Disabilities / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009483:Neuropsychological Tests; D011110:Polymorphism, Genetic; D016548:Prosencephalon / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D014446:Tyrosine 3-Monooxygenase; C000593198:COMT protein, mouse; D002394:Catechol O-Methyltransferase; D004298:Dopamine