A new study led by researchers from the University of Michigan demonstrate that mice with a variant associated with Attention deficit hyperactivity disorder (ADHD) adopt an inattentive phenotype similar to that seen in humans.
Results of the study, published in The Journal of Neuroscience, indicate that a variant (Val89) in the choline transporter (CHT) gene reduces the rate of choline uptake and the capacity to sustain acetylcholine production during attention-demanding conditions. Mice with the variant also show diminished cognitive performance when faced with attentional challenges.
Prior work by the team has shown that this variant is associated with heightened distractibility in humans, though whether the variant is itself causal was not clear.
Evidence from this team’s mouse studies provide further proof that Val89 drives increased vulnerability to distraction and provides a mechanistic basis for the diminished frontal cortex activation observed in Val89-expressing humans.
After using CRISPR/Cas9 to change the gene encoding the neuronal CHT, the researchers searched for physiological changes in the brain, focusing on the ability to sustain production and release of acetylcholine, which is synthetized from choline.
In humans, disruption of acetylcholine signaling impairs capacity to filter distractors and to perform focus-demanding tasks. A total loss of CHT function in mice and people leads to early death due to the role acetylcholine plays in muscle contraction, particularly the muscles that control breathing. Lesser reductions in CHT activity allows for normal growth and movement, but mice with these changes exhibit premature fatigue when made to run on a treadmill. The new study reveals that CHT-deficient mice also show signs of mental fatigue.
“Our mouse studies, along with prior behavioral and brain imaging studies, indicate that a single copy of the variant is sufficient to change acetylcholine availability and its resulting cognitive effects,” said Randy D. Blakely, a co-author of the study and executive director of the Florida Atlantic University (FAU) Stiles-Nicholson Brain Institute, at FAU’s Schmidt College of Medicine.
Blakely added that, “Seeing effects from a single copy of Val89 suggests that choline transport may be mediated by a pair of CHT proteins such that one poorly functioning copy can impact the normal function of the other, leading to stronger effects than expected from simply having one copy compromised.”
This finding has been reported before in people with neuromuscular disorder causing CHT mutations, but this also appears to be the case for brain function.
“Val89 mice lack cognitive flexibility in response to an attentional challenge,” said Eryn Donovan, lead author of the study and a graduate student in the Department of Psychology, University of Michigan. “Our findings from this mouse model suggest the potential for a more complete investigation of the effects of the CHT Val89 mutation in the brain as well as the development of therapeutic strategies for those with disrupted acetylcholine signaling.”
According to the United States Centers for Disease Control and Prevention, the estimated number of children diagnosed with ADHD according to a 2016 parent survey was 6.1 million. This same survey shows that 6 in 10 children with ADHD had at least one other mental, emotional or behavioral disorder and 62 percent were taking ADHD medication. Although ADHD most often occurs in children, it also can be diagnosed in adulthood.
