Scientists Propose New Way to Diagnose Dopamine-Linked Disorders Using Mouse with ADHD Traits

Newswise — If the “eyes are the window to the soul,” then a series of studies from a Florida Atlantic University laboratory suggests that they may also be a window into diagnosing and treating attention-deficit/hyperactivity disorder (ADHD) and other dopamine-linked neuropsychiatric disorders.

ADHD is the most prevalent inherited neurobehavioral childhood disorder that affects between 4 to 12 percent of school-aged children in the United States. Changes in the neurochemical dopamine are believed to contribute to this disorder as well as bipolar disorder and autism spectrum disorder (ASD). Individuals diagnosed with these disorders have been found to express a rare, functional alteration in the dopamine transporter. ADHD is more prevalent in relatives of bipolar disorder subjects and many individuals diagnosed with ASD meet clinical criteria for ADHD, suggesting that the three disorders, deep down, share common origins.

Several years ago, researchers from the FAU Brain Institute, led by Randy D. Blakely, Ph.D., executive director of the FAU Brain Institute and a professor of biomedical science in FAU’s Charles E. Schmidt College of Medicine, identified a rare, functional mutation in the dopamine transporter, DAT Val559, in two boys with ADHD. The mutation, which has previously been identified in subjects with bipolar disorder, was then identified in subjects with ASD. Blakely’s team hypothesized that elucidating the impact of the variant could provide new insights into how brain dopamine dysfunction drives mental illness, including those linked to ADHD, autism and bipolar disorder.

With mice whose DNA has been modified to express the DAT Val559 mutation, Blakely’s team is evaluating the molecular, cellular and circuit level disturbances that can increase risk for behavioral disorders, including changes in cognitive capacities, attention and impulsivity.

In a study recently published in the journal Behavioural Brain Research, Blakely’s graduate student, Gwynne Davis, was able to demonstrate changes in these mice that indicate impulsivity and an elevated motivation for reward. Impulsivity can be tested in a number of ways in mice, such as tasks that require the mouse to respond before a set time has elapsed. The DAT Val559 mice show a difficulty in waiting to receive rewards. Further studies indicate that this “waiting impulsivity” derives from an increased motivation to receive reward.

“While impulsivity is one of the core components of an ADHD diagnosis, and can be present in subjects with ASD and bipolar disorder, the source of that impulsivity remains unclear, and the type of impulsivity these subjects demonstrate can vary greatly,” said Blakely. “Our studies support the idea that disrupted dopamine signaling contributes to these disorders and may lead to more effective treatments.”

To take studies of the DAT Val559 model toward improved diagnostics, Blakely’s group decided to look into the eyes of his mice, measuring their response to light. Results of this study were recently published in the Journal of Neurobehavioral Disorders. Recognizing that dopamine is critical to the ability of the retina to sense changes in light, Blakely’s team, along with collaborators Heng Dai and Douglas G. McMahon, Ph.D., both at Vanderbilt University, used a noninvasive approach to monitor the retinal responses to light in the DAT Val559 mice.

They discovered that these animals show readily detectible changes in retinal responses that are consistent with increased dopamine signaling. Interestingly, this effect was found to be sex-dependent, detected in males but not females, which Blakely speculates may be related to the male predominance of ADHD and ASD diagnoses.

“Interestingly, there is evidence that patients with these disorders exhibit impaired retinal and visual functions,” said Blakely. “This suggests that altered dopamine signaling in the retina may be controlled by some of the same molecular disturbances that cause these disorders.”

Results from the study also suggest that monitoring retinal responses to light in humans may reveal physiological signatures of these disorders, providing an approach to earlier detection and treatment. Although rare, Blakely believes the DAT Val559 variant is representative of a more general abnormality underlying ADHD and ASD.

This research was supported in part by grants from the National Institutes of Health (MH105094, MH107132 and GM117650).

- FAU -

About the Charles E. Schmidt College of Medicine:

FAU’s Charles E. Schmidt College of Medicine is one of approximately 151 accredited medical schools in the U.S. The college was launched in 2010, when the Florida Board of Governors made a landmark decision authorizing FAU to award the M.D. degree. After receiving approval from the Florida legislature and the governor, it became the 134th allopathic medical school in North America. With more than 70 full and part-time faculty and more than 1,300 affiliate faculty, the college matriculates 64 medical students each year and has been nationally recognized for its innovative curriculum. To further FAU’s commitment to increase much needed medical residency positions in Palm Beach County and to ensure that the region will continue to have an adequate and well-trained physician workforce, the FAU Charles E. Schmidt College of Medicine Consortium for Graduate Medical Education (GME) was formed in fall 2011 with five leading hospitals in Palm Beach County. In June 2014, FAU’s College of Medicine welcomed its inaugural class of 36 residents in its first University-sponsored residency in internal medicine and graduated its first class of internal medicine residents in 2017.

About the FAU Brain Institute:

Inaugurated in 2016 on the John D. MacArthur Campus in Jupiter, Fla., the FAU Brain Institute supports research, education and community outreach among more than 100 faculty level researchers at FAU and its affiliate research centers. One of FAU’s four pillars that guide the University’s goals and strategic actions, the Institute seeks to unlock the secrets of brain development, function and plasticity and how the mechanisms uncovered can be compromised to drive devastating brain disorders. From the study of neuronal development and signaling to investigations of brain diseases including addiction, autism, Parkinson’s and Alzheimer’s disease, researchers from FAU’s Brain Institute seek to generate knowledge that benefits society. For more information about the Institute and its members, visit www.ibrain.fau.edu.

About Florida Atlantic University:

Florida Atlantic University, established in 1961, officially opened its doors in 1964 as the fifth public university in Florida. Today, the University, with an annual economic impact of $6.3 billion, serves more than 30,000 undergraduate and graduate students at sites throughout its six-county service region in southeast Florida. FAU’s world-class teaching and research faculty serves students through 10 colleges: the Dorothy F. Schmidt College of Arts and Letters, the College of Business, the College for Design and Social Inquiry, the College of Education, the College of Engineering and Computer Science, the Graduate College, the Harriet L. Wilkes Honors College, the Charles E. Schmidt College of Medicine, the Christine E. Lynn College of Nursing and the Charles E. Schmidt College of Science. FAU is ranked as a High Research Activity institution by the Carnegie Foundation for the Advancement of Teaching. The University is placing special focus on the rapid development of critical areas that form the basis of its strategic plan: Healthy aging, biotech, coastal and marine issues, neuroscience, regenerative medicine, informatics, lifespan and the environment. These areas provide opportunities for faculty and students to build upon FAU’s existing strengths in research and scholarship. For more information, visit www.fau.edu.