Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum

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.The catechol-O-methyl transferase (COMT) enzyme degrades catecholamines, including dopamine. A single nucleotide polymorphism in the human COMT gene (Val 158 ) increases the thermostability of the enzyme-thereby increasing its level of activity compared to the 158

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

“…The role of COMT is well established in low-DAT density brain regions, such as the PFC, 38,39 whereas there are contrasting findings in the striatum. 40,41 The present data also support a role of COMT in striatal DA function. Despite the reduced expression of COMT and consequent increase in DOPAC we saw no changes in tissue content of DA and HVA, NA or 5-HT.…”

Genotype-Dependent Effects of COMT Inhibition on Cognitive Function in a Highly Specific, Novel Mouse Model of Altered COMT Activity

“…The COMT knockout mouse shows increased anxiety and an exaggerated reactivity to acute stress, compared with wild-type animals (Desbonnet et al , 2012; Gogos et al , 1998; Papaleo et al , 2008, 2012). These findings are in keeping with the demonstration of reduced anxiety in one line of COMT-overexpressing mice (Papaleo et al , 2008), although a second, forebrain-specific COMT -overexpressing mouse line did not show this change (Simpson et al , 2014). …”

“…Mice with genetically altered COMT activity have consistently shown alterations in at least some aspects of cognitive function. For example, COMT knockout mice show improvements, and COMT -overexpressing mice impairments, in tests of attentional set shifting and spatial working memory (Babovic et al , 2008; Papaleo et al , 2008; Simpson et al , 2014). Consistent with these earlier findings are data from recently developed, humanized COMT transgenic mice that carry the human Val- or Met- COMT open reading frames on a COMT -null background: humanized Met-COMT mice show superior spatial working memory, compared with Val-COMT mice (Risbrough et al , 2014).…”

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

“…Notably different laminar patterns of COMT mRNA expression in pyramidal neurons has been observed in SZ cases compared to controls (Matsumoto et al, 2003). Association of COMT with various cognitive functions has been reported (Simpson et al, 2014). DISC1 is a major risk gene in SZ with an important role in neuronal maturation, proliferation, migration, positioning, differentiation, dendritic growth, axonal outgrowth, and synaptic plasticity through its direct or indirect interactions with various signaling pathways in brain including AKT, GABA, GSK3β, WNT, and NMDA-R (Wu et al, 2013).…”