TY - JOUR
T1 - Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice
AU - Papaleo, Francesco
AU - Crawley, Jacqueline N.
AU - Song, Jian
AU - Lipska, Barbara K.
AU - Pickel, Jim
AU - Weinberger, Daniel R.
AU - Chen, Jingshan
PY - 2008/8/27
Y1 - 2008/8/27
N2 - 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.
AB - 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.
KW - Attentional set shifting
KW - Calcium/calmodulin-dependent kinase
KW - Genes
KW - Mice
KW - Stress
KW - Working memory
UR - http://www.scopus.com/inward/record.url?scp=52049116298&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=52049116298&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2077-08.2008
DO - 10.1523/JNEUROSCI.2077-08.2008
M3 - Article
C2 - 18753372
AN - SCOPUS:52049116298
SN - 0270-6474
VL - 28
SP - 8709
EP - 8723
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 35
ER -