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

• 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Keyword

Animals

Catechol O-Methyltransferase

genetics

metabolism

Cognition

physiology

Compulsive Behavior

genetics

metabolism

Corpus Striatum

metabolism

Dopamine

metabolism

Dopamine Plasma Membrane Transport Proteins

metabolism

Impulsive Behavior

Learning

physiology

Learning Disorders

genetics

metabolism

Male

Memory Disorders

genetics

metabolism

Memory

Short-Term

physiology

Mice

Mice

Inbred C57BL

Mice

Transgenic

Models

Animal

Motor Activity

genetics

physiology

Neuropsychological Tests

Polymorphism

Genetic

Prosencephalon

metabolism

Tyrosine 3-Monooxygenase

metabolism

Publication and Content Type

ref (subject category)

art (subject category)