Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice

Francesco Papaleo, Jacqueline Crawley, Jian Song, Barbara K. Lipska, Jim Pickel, Daniel R. Weinberger, Jingshan Chen

Research output: Contribution to journalArticle

243 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8709-8723
Number of pages15
JournalJournal of Neuroscience
Volume28
Issue number35
DOIs
StatePublished - Aug 27 2008
Externally publishedYes

Keywords

  • Attentional set shifting
  • Calcium/calmodulin-dependent kinase
  • Genes
  • Mice
  • Stress
  • Working memory

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Fingerprint Dive into the research topics of 'Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice'. Together they form a unique fingerprint.

  • Cite this