Public Release:  Gene enhances prefrontal function at a price

NIH/National Institute of Mental Health

Studies of a gene that affects how efficiently the brain's frontal lobes process information are revealing some untidy consequences of a tiny variation in its molecular structure and how it may increase susceptibility to schizophrenia. People with a common version of the gene associated with more efficient working memory and frontal lobe information processing may pay a penalty in adverse responses to amphetamine, in heightened anxiety and sensitivity to pain. Yet, another common version may slightly bias the brain toward a pattern of neurochemical activity associated with psychosis, report researchers at the National Institutes of Health (NIH).

Everyone inherits two copies of the catecho-O-methyltransferase (COMT) gene, one from each parent. It codes for the enzyme that metabolizes neurotransmitters like dopamine and norepinephrine and comes in two common versions. One version, met, contains the amino acid methionine at a point in its chemical sequence where the other version, val, contains a valine. Depending on the mix of variants inherited, a person's COMT genes can be typed met/met, val/val, or val/met.

"Since both versions of the COMT gene are common in the population - they've been conserved as the human brain evolved -- it makes sense that each would confer some advantages and disadvantages," explained Daniel Weinberger, M.D., National Institute of Mental Health (NIMH), whose research team, headed by Venkata Mattay, M.D., reports on how the variants affect the brain's response to amphetamine in the May 13, 2003 Proceedings of the National Academy of Sciences, already published online.

"Genes don't directly encode for psychopathology, hallucinations, delusions and panic attacks. Rather, there is a very complicated path between a gene's influence on the regulation and function of a protein and such psychiatric phenomena," added Weinberger. "We're especially interested in the COMT gene variants because they provide insight into how a gene affects the way the brain processes information - and perhaps how this might ultimately increase susceptibility to schizophrenia." A series of brain imaging studies by the NIMH researchers have shown that frontal lobe information processing is impaired in schizophrenia.

Two years ago, the NIMH researchers reported that people with the val/val variant had evidence of reduced prefrontal dopamine activity and less efficient prefrontal information processing, along with slightly increased risk for schizophrenia. People with val/met had more efficient prefrontal function, and people with met/met the most efficient. The met variant results in 3-4 times weaker enzyme action, which is thought to allow for more dopamine activity in the prefrontal cortex, as the neurotransmitter breaks down more slowly.

Since amphetamine boosts dopamine activity in the prefrontal cortex, the researchers predicted that the drug would, in effect, correct a deficiency in people with val/val - that they would experience more optimal levels of dopamine and perform better on working memory and other cognitive tasks known to depend on the prefrontal cortex. They further predicted that people with met/met on amphetamine would perform worse and their frontal lobes would function less efficiently as task difficulty increased.

In what the researchers believe is the "first demonstration in humans of a genetic explanation for individual differences in the brain response to amphetamine," they asked 27 normal volunteers - 10 val/val, 11 val/met, and 6 met/met - to perform working memory and other "executive" (abstract reasoning, planning) tasks while their brain activity was monitored using functional magnetic resonance imaging (fMRI). In the double-blind, crossover design, subjects were given either amphetamine or placebo prior to performing the tasks. Efficiency, or neuronal signal-to-noise ratio, was gauged by how hard the brain had to work to maintain a given level of task performance.

As predicted, regardless of how hard the working memory task was, val/val subjects on amphetamine showed more efficient frontal lobe function - their brains didn't have to work as hard as they did on placebo to perform quickly and accurately. By contrast, the efficiency, accuracy and reaction time of met/met subjects on amphetamine dropped off precipitously, from placebo levels, when the task reached the hardest of three levels of difficulty, suggesting that their information processing was compromised. Another test of frontal lobe function showed a similar pattern. Val/val subjects on amphetamine appeared similar to met/met individuals at baseline. Met/met subjects on amphetamine performed worse than subjects with val/val at baseline.

These results fit a model in which dopamine activity needs to be neither too low nor too high for optimal prefrontal functioning. The brain performs most efficiently when dopamine activity is at a moderate level corresponding to the top of an upside-down "U" (see diagram below).

"The combined effects on dopamine levels of amphetamine and high working memory load push individuals with the met/met genotype beyond the critical threshold at which compensation can be made," suggest the researchers. They note evidence from other studies that too much dopamine activity in the prefrontal cortex may disorganize neural networks by activating inhibitory mechanisms.

Amphetamines and other drugs that affect prefrontal dopamine systems are used to treat Attention Deficit Hyperactivity Disorder (ADHD), and other psychiatric illnesses, and some people respond better than others to these medications. Noting that it has been difficult to predict, in advance, which patients might show adverse responses, the researchers suggest that, after further research, COMT gene type may become a relevant factor to consider in managing treatment. About 15-20 percent of individuals in populations of European ancestry have the met/met COMT gene type.

In other recent studies, researchers supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) have found an association between met/met and increased anxiety -- and heightened sensitivity to pain. Yet, the emerging theme from what's being learned about effects of the COMT gene val/met genetic variation, or polymorphism, is that it cuts both ways. NIMH's Weinberger says preliminary evidence suggests that having even one met predicts a better response on working memory tests in schizophrenia patients after treatment with an antipsychotic medication. Moreover, there is new evidence about how the val variant may increase risk for such psychotic illness.

Mayada Akil, M.D., Joel Kleinman, M.D., and colleagues in the NIMH Clinical Brain Disorders Branch, examined expression of the gene that codes for tyrosine hydroxylase, the enzyme that makes dopamine, in the brains of 23 deceased normal subjects. In the March 15, 2003 Journal of Neuroscience, they report that the gene turns-on more in neurons projecting to the striatum (an area in the middle of the brain) in people who inherited two copies of the COMT val variant than in those with only one copy of the val variant. The higher expression of the tyrosine hydroxylase gene reflects higher dopamine synthesis, and presumably, higher activity of dopamine neurons.

Evidence suggests that the val variant likely triggers more dopamine activity in the striatum indirectly, by dampening prefrontal dopamine activity. A resulting weak prefrontal signal-to-noise ratio gets telegraphed to the lower brain areas by other neurons projecting from the prefrontal cortex, disinhibiting the dopamine neurons projecting to the striatum, the researchers speculate. Such a seesaw pattern of decreased dopamine in the prefrontal cortex and increased dopamine in the striatum has been implicated as a mechanism related to schizophrenia and psychosis in humans. Animal studies modeling possible brain mechanisms in schizophrenia have also observed this pattern.

These val-influenced variations "slightly bias humans toward the expression of two biological phenomena associated with schizophrenia: abnormal prefrontal function and up-regulated striatal dopamine activity," suggest the researchers.

Many mysteries still surround the COMT gene's possible role in schizophrenia and other psychiatric illness. For example, last Fall a team of researchers in Israel reported finding strong associations between other parts of the COMT gene and schizophrenia.

Researchers who participated in the amphetamine study also included: Drs. Terry Goldberg, Francesco Fera, Ahmad Hariri, Alessandro Tessitore, Michael Egan, Bhaskar Kolachana, Joseph Callicott, NIMH. Also participating in the postmortem study were: Drs. Bhaskar Kolachana, Debora Rothmond, Thomas Hyde, Daniel Weinberger, NIMH.


NIMH and NIAAA are part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

An inverted "U" models the effects of COMT gene type, difficulty of the working memory task, and amphetamine on dopamine (DA) activity in the prefrontal cortex. By boosting dopamine, amphetamine shifts people who have inherited two copies of the val variant (green) -- who normally have relatively poorer prefrontal function, greater COMT activity, and presumably less dopamine activity - to the right, and more optimal functioning. Amphetamine shifts people with two copies of met (red) - who normally are at an optimal position - to less efficient functioning as the task reaches the most difficult level (3-Back) and places a greater load on the brain.

Source: NIMH Clinical Brain Disorders Branch.

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