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The Journal of Neuroscience, August 27, 2008, 28(35):8709-8723; doi:10.1523/JNEUROSCI.2077-08.2008

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Behavioral/Systems/Cognitive
Genetic Dissection of the Role of Catechol-O-Methyltransferase in Cognition and Stress Reactivity in Mice

Francesco Papaleo,¹ Jacqueline N. Crawley,² Jian Song,¹ Barbara K. Lipska,¹ Jim Pickel,³ Daniel R. Weinberger,¹ and Jingshan Chen¹

¹Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, Maryland 20892, and Laboratories of ²Behavioral Neuroscience and ³Genetics, National Institute of Mental Health Bethesda, Maryland 20892

Correspondence should be addressed to Daniel R. Weinberger at his present address: Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Room 4S-235, 10 Center Drive, Bethesda, MD 20892. Email: weinberd{at}mail.nih.gov

The COMT (catechol-O-methyltransferase) gene has been linked to a spectrum of human phenotypes, including cognition, anxiety, pain sensitivity and psychosis. Doubts about its clinical impact exist, however, because of the complexity of human COMT polymorphism and clinical variability. We generated transgenic mice overexpressing a human COMT-Val polymorphism (Val-tg), and compared them with mice containing a null COMT mutation. Increased COMT enzyme activity in Val-tg mice resulted in disrupted attentional set-shifting abilities, and impaired working and recognition memory, but blunted stress responses and pain sensitivity. Conversely, COMT disruption improved working memory, but increased stress responses and pain sensitivity. Amphetamine ameliorated recognition memory deficits in COMT-Val-tg mice but disrupted it in wild types, illustrating COMT modulation of the inverted-U relationship between cognition and dopamine. COMT-Val-tg mice showed increased prefrontal cortex (PFC) calcium/calmodulin-dependent protein kinase II (CaMKII) levels, whereas COMT deficiency decreased PFC CaMKII but increased PFC CaMKKβ and CaMKIV levels, suggesting the involvement of PFC CaMK pathways in COMT-regulated cognitive function and adaptive stress responses. Our data indicate a critical role for the COMT gene in an apparent evolutionary trade-off between cognitive and affective functions.

Key words: working memory; attentional set shifting; genes; mice; stress; calcium/calmodulin-dependent kinase

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Received May 5, 2008; revised June 23, 2008; accepted July 9, 2008.

Correspondence should be addressed to Daniel R. Weinberger at his present address: Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Room 4S-235, 10 Center Drive, Bethesda, MD 20892. Email: weinberd{at}mail.nih.gov

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