Generation and Characterization of Humanized Mice Carrying COMT158 Met/Val Alleles

Abstract

The Val158Met polymorphism of human catechol-o-methyltransferase (COMT) is one of the most well-studied single-nucleotide polymorphisms in neuropsychiatry; however, findings are inconsistent due to human genetic heterogeneity. We created the first 'humanized' COMTVal158Met mouse lines, which carry either human COMT Val or Met alleles via gene targeting. The 'humanized' mouse model enables strict comparison of the physiological functions of the two alleles. Consistent with human observation, Met/Met mice exhibited a 30% reduction in enzymatic activity compared with Val/Val mice. On the basis of the reported differences in human Met and Val carriers across working memory, fear processes and sensorimotor gating, we examined these functions between sibling Met/Met and Val/Val mice. Val/Val mice exhibited robust reductions in spatial working memory compared with Met/Met mice in both sexes, with tolcapone treatment significantly reversing the Val/Val alternation deficits. Sex effects were observed in other behaviors, with male Val/ Val mice exhibited lower prepulse inhibition compared with Met/Met mice, whereas female mice exhibited the opposite phenotype. Female but not male Met/Met mice exhibited reduced contextual fear, increased cued fear, and reduced extinction recall. Thus, these mice (1) support the argument that human COMT Val158Met polymorphism modulates behavioral functions and most importantly (2) exhibit the expected treatment effects supporting the 'inverted U shaped' dose response of catecholamine signaling on cognitive function. This model will be invaluable for understanding the effects of human COMT Val158Met polymorphism on cortical development and behavioral functions, and how this polymorphism modulates treatment response.

Brain catechol-O-methyltransferase (COMT) inhibition by tolcapone counteracts recognition memory deficits in normal and chronic phencyclidine-treated rats and in COMT-Val transgenic mice

“…COMT is thought to be an important mechanism for the termination of dopamine signaling in the cortex, owing to the paucity of dopamine transporters in this brain region, and cortical dopaminergic activity is thought to underlie many aspects of cognition (Lewis et al, 2001; Clark et al 2014). There is a large body of preclinical research indicating that COMT inhibition improves cognitive function across multiple domains (Khromova et al, 1997; Tunbridge et al, 2004; Lapish et al, 2009; Laatikainen et al, 2012; Risbrough et al, 2014), therefore it seems plausible that central COMT inhibition may impact on different brain areas beyond the cortex or hippocampus. Additionally, data from small clinical studies suggest that tolcapone improves cognitive function in healthy individuals and people with Parkinson’s Disease (Gasparini et al, 1997; Apud et al, 2007).…”

Animal models of bipolar mania: The past, present and future

“…Now with readily available and more affordable genome editing tools, such as TALEN or CRISPR/Cas9 technologies, investigators can recreate the precise genetic polymorphisms associated with BD. For example, ‘humanized’ mice carrying either Val or Met alleles in the catechol-o-methyltransferase (COMT) gene, an enzyme that degrades cathecholamines, dopamine, epinephrine, and norepinephrine, support the human genetic findings suggesting the human COMT Val158Met polymorphism modulates behavioral and cognitive functioning (Risbrough et al, 2014). ‘Humanized’ rodent models can systematically investigate the effects of risk loci on the developmental and behavioral factors of BD (Malkesman et al, 2009).…”

Investigating the mechanism(s) underlying switching between states in bipolar disorder

“…Other genes linked to psychiatric conditions have been recreated and inserted into mice, such as the disrupted in schizophrenia 1 (DISC1)/boymaw transfusion gene (Ji et al, 2014) that has been related to schizophrenia and BD. Furthermore, a key element of catecholaminergic homeostasis in the prefrontal cortex is the catecho-methyl-transferase (COMT) gene (Allen et al, 1997; Risbrough et al, 2014; Tunbridge et al, 2012). COMT clears dopamine in the prefrontal cortex and the allelic variants of COMT result in faster (val/val) or slower (met/met) dopamine clearance (Allen et al, 1997).…”