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GENETIC VARIATION AND NATURAL AGING ACT INDEPENDENTLY TO REGULATE BRAIN FUNCTION

 

Lieber researchers have discovered that variability in a gene for the dopamine transporter (DAT)—a protein that directly controls the availability of the neurotransmitter dopamine—modulates the function of a subcortical brain area called the striatum. 

Researchers at the Lieber Institute for Brain Development (LIBD), with colleagues, have discovered that variability in a gene for the dopamine transporter (DAT)—a protein that directly controls the availability of the brain chemical dopamine—modulates the function of a subcortical brain area called the striatum. The striatum is involved in working memory, whose malfunction plays a role in a range of psychiatric illnesses, including schizophrenia. While the function of the striatum is known to decline with age, the researchers found no evidence that aging influences the effect of the DAT genetic variation.

DAT governs dopamine availability within the striatum by regulating the chemical’s movement from the synapse back into neurons. Expression levels of DAT are controlled, in part, by variation in the number of repeats—either 9 or 10—of small snippets of genetic code in a specific region of the gene that encodes DAT. The 10-repeat genotype has been associated with greater expression of DAT than the 9-repeat genotype, resulting in lower extracellular striatal dopamine levels and, therefore, decreased striatal activity in 10-repeat carriers.

“Our findings add to the evidence for a role of dopamine in the modulation of cortico-striatal networks underlying cognition during adulthood, functions that are frequently perturbed in psychiatric illness.”

The research team genotyped 54 healthy subjects of various age for the DAT gene. The subjects, roughly half of which had the 9-repeat genotype while the other half had the 10-repeat genotype, performed a working memory test that reflects a cognitive process known to strongly activate the neural circuitry connecting the striatum and the cortex.

Consistent with previous findings, the team observed an age-related decrease in striatal activity during the working memory task, as measured by functional brain imaging. The researchers also saw decreased striatal activity in subjects with the 10-repeat genotype relative to the 9-repeat carriers. In contrast, the 10-repeat carriers showed increased striatal-hippocampal connectivity, perhaps reflecting a compensatory mechanism to make up for their decreased dopamine levels. However, the rate of the age-related decline in striatal function was similar across 10-repeat and 9-repeat carriers. These results, published August, 2015 in the European Journal of Neuroscience, suggest that age and genetic variation in the DAT gene independently modulate striatal function.

Senior author on the paper, Venkata (Anand) Mattay, M.D., Investigator at LIBD, explains the importance of the findings: “Dopamine modulation of striatal function is critical for executive functions such as working memory. The goal of the present study was to investigate the effects of aging and a specific genetic variation of the dopamine transporter on the neural activity and functional connectivity of the striatum during working memory updating. Our results showed both an age-related decrease in striatal activity and an effect of the genetic variation. Our findings add to the evidence for a role of dopamine in the modulation of cortico-striatal networks underlying cognition during adulthood, functions that are frequently perturbed in psychiatric illness.”