New research may explain why symptoms of ADHD and ASD present differently between sexes

A recent study found that a rare human gene variant, which is featured in many neuropsychiatric disorders, impacted the brain regions and behaviors of male and female mice differently. According to researchers, this may explain why symptoms of neuropsychiatric disorders like attention- deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often differ between males and females.

The study, published in the journal, Molecular Psychiatry, was led by Randy Blakely, PhD, professor of biomedical science at Schmidt College of Medicine at Florida Atlantic University (FAU) and executive director of the FAU Stiles-Nicholson Brain Institute in Boca Raton, Florida. For the investigation, Blakely teamed up with neuroscientists from FAU and the University of North Dakota School of Medicine and Health Sciences in Grand Forks, North Dakota, to discover whether a rare genetic variant reacted differently between male and female rodent models.

In a previous study, Blakely and his team analyzed changes in dopamine regulatory genes in children diagnosed with ADHD and identified a genetic variant that distinctly altered the function of the dopamine transporter (DAT). Rather than removing dopamine from synapses, DAT’s normal function, the DAT variant spit out dopamine, failing to efficiently remove it from the cell, according to the study. Blakely and other researchers from the prior study also found that the DAT variant was associated with changes in behavior and drug responses in the mice, altering pathways related to locomotor activation, habitual behavior, and impulsivity. These tests, however, were only conducted on male mice.

For this study, Blakely and his team conducted experiments on both male and female mice, and compared their behavioral changes related to the DAT variant. The results showed the DAT variant had region-specific, sex-based patterns of DAT regulation. Upon further research, scientists discovered these differences were due to a circuit flip in how brain pathways in males and females use a key DAT regulator protein.

The study’s results also showed that these sex-dependent changes to DAT regulation patterns also impacted the behavior of male and female mice with the variant. In comparison to wildtype females, the females with the mutation appeared more anxious and struggled more with novelty recognition. Males with the mutation were less social and demonstrated increased perseverative behavior, behaviors not observed in the female mice.

According to researchers, these results suggest that genetic mutations associated with neuropsychiatric disorders may impact males and females differently and cause varying behavioral changes.

“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 first author of the report, Adele Stewart, PhD, a professor of biomedical science at Schmidt College of Medicine.