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.
Subject(s)
Catechol O-Methyltransferase/metabolism , Corpus Striatum/metabolism , Dopamine/metabolism , Learning Disabilities/metabolism , Learning/physiology , Animals , Catechol O-Methyltransferase/genetics , Cognition/physiology , Compulsive Behavior/genetics , Compulsive Behavior/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Impulsive Behavior , Learning Disabilities/genetics , Male , Memory Disorders/genetics , Memory Disorders/metabolism , Memory, Short-Term/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Animal , Motor Activity/genetics , Motor Activity/physiology , Neuropsychological Tests , Polymorphism, Genetic , Prosencephalon/metabolism , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Cognitive deficits in schizophrenia are thought to derive from a hypofunction of the prefrontal cortex (PFC), but the origin of the hypofunction is unclear. To explore the nature of this deficit, we genetically modified mice to model the increase in striatal dopamine D(2) receptors (D(2)Rs) observed in patients with schizophrenia. Previously, we reported deficits in spatial working memory tasks in these mice, congruent with the working memory deficits observed in schizophrenia. However, patients with schizophrenia suffer from deficits in many executive functions, including associative learning, planning, problem solving, and nonspatial working memory. We therefore developed operant tasks to assay two executive functions, conditional associative learning (CAL) and nonspatial working memory. Striatal D(2)R-overexpressing mice show a deficit in CAL because of perseverative behavior, caused by interference from the previous trial. D(2)R up-regulation during development was sufficient to cause this deficit, because switching off the transgene in adulthood did not rescue the phenotype. We validated prefrontal dependency of CAL by using neurotoxic lesions. Lesions of the medial PFC including the anterior cingulate, infralimbic, and prelimbic cortices impair CAL because of increased interference from previously rewarded trials, exactly as observed in D(2)R transgenic mice. In contrast, lesions restricted to the infralimbic and prelimbic cortices have no effect on CAL but impair performance in the nonspatial working memory task. These assays not only give us insight into how excess striatal D(2)Rs affect cognition but also provide tools for studying cognitive endophenotypes in mice.
