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ADHD Gene Variant Affects Different Brain Regions in Males, Females
Male and female mice engineered with a gene variant associated with attention-deficit/hyperactivity disorder (ADHD) experienced different brain and behavioral effects, according to a study published online in Molecular Psychiatry.
“While we understand that there are biological differences between rodent and human brains, studies like ours provide an important opportunity to explore biological mechanisms that contribute to sex differences in risk for neuropsychiatric diseases,” said first author Adele Stewart, PhD, of Florida Atlantic University, Jupiter, Florida.
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In a previous study of children with ADHD, a team led by Randy Blakely, PhD, professor of biomedical science in the Florida Atlantic University Schmidt College of Medicine and executive director of the university’s Stiles-Nicholson Brain Institute, identified a gene variant that alters the function of the dopamine transporter (DAT). DAT typically functions as a nanoscale dopamine vacuum cleaner that works to remove dopamine from synapses. When the DAT variant was expressed in cells, however, it “ran backward” and spit out dopamine rather than remove it.
When the team engineered the variant into the genome of mice, changes in behavior and drug responses predicted by the abnormal DAT behavior occurred, with an emphasis on traits linked to pathways related to locomotor activation, habitual behavior, and impulsivity. However, the studies were performed exclusively with male mice.
The current study sought to investigate how female mice handled the DAT mutation. According to the findings, females show effects in brain regions unaffected in males. The behavioral consequences of this region-specific, sex-biased pattern of DAT regulation were profound, researchers explained, with the mutant DAT altering behaviors in a pattern unique to each sex. Specifically, female mice with the mutation appeared more anxious and had issues with novelty recognition compared with other female mice. Males, on the other hand, were less social and displayed increased perseverative behavior—changes not seen in female mice.
“What our study shows is that behavioral generalizations across the sexes may limit diagnosis of mental illness, particularly if one sex translates alterations into outward signs such as hyperactivity and aggression versus more internal manifestations such as learning, memory and mood, even when the same molecular pathology is at work,” said Dr Stewart.
“What is more, our work supports the idea that treatment strategies should be cognizant of the sex-dependence of neuronal signaling mechanisms rather than assuming treatment that what is good for the goose is good for the gander. In fact, such therapies may either not be good for the gander at all, or good for a completely different kind of disorder.”
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