ADHD: A gene makes fish larvae hyperactive

Its scientific name is lphn3. In humans, this gene lies on chromosome 4 and codes the protein latrophilin 3, which may play a role as a synaptic protein and receptor in the brain when the typical characteristics of attention deficit hyperactivity disorder emerge: people affected struggle to focus their attention over longer periods, they are easily distracted, they tire quickly, they often react impulsively, and they demonstrate obvious motor restlessness.

Focus on the latrophilin 3 gene

“Latrophilin 3 has long been suspected of being partly responsible for the typical characteristics of ADHD. Though, not all that much is known to date about its role within the physiological processes of the nervous system,” says Professor Klaus-Peter Lesch.
Lesch is Chairman of the Department of Molecular Psychiatry and Spokesman for the ADHD Clinical Research Group at the University of Würzburg’s Department of Psychiatry, Psychosomatics, and Psychotherapy. He has had his sights on this protein for a few years now. And he is not alone: “Researchers from the USA and Spain have recently shown that a particular variant of the latrophilin 3 gene is frequently found in the genetic material of patients who are still suffering from ADHD in adulthood,” says Lesch. What is more, the gene has also been identified as one of a total of 86 risk genes that are suspected of triggering drug dependency. The occurrence of drug dependency is above average in ADHD patients.

Experiments on zebrafish larvae

To improve understanding of the role that latrophilin 3 plays in the development of ADHD symptoms, Lesch and scientists from the Institute of Neurobiology in Gif-sur-Yvette, France, conducted experiments with zebrafish larvae. “Zebrafish have now become the standard model in science for examining the genetic fundamentals of brain development and behavior,” explains Lesch.

In their experiments, the researchers inhibited the lphn3 gene during a particular development phase and then examined the behavior of the fish larvae. They concentrated primarily on the movement activity of the larvae as an easily measurable expression of motor restlessness.
The results

The outcome: “We observed a significant increase in swimming distances and average speed in these fish larvae compared to a control group,” write the authors. This effect was also evident during the night-time sleep phases – in the same way as human ADHD patients can demonstrate hyperactivity symptoms in their sleep.

The scientists believe that this increased urge to move was caused by a fault in the development of the neural networks of the dopamine system in the brain of the zebrafish larvae. Dopamine is a transmitter that is responsible for, among other things, making movements happen harmoniously and optimizing certain mental processes. The larvae in which the lphn3 gene had been inhibited consequently developed considerably fewer nerve cells that produce dopamine. The more pronounced the urge to move was in the fish, the lower the number was of these specific neurons.

Methylphenidate helps

If zebrafish demonstrate symptoms typical of ADHD under these conditions, can they too be treated with the usual medications? This question was also explored by the researchers. One of the most effective drugs for treating ADHD in humans is methylphenidate – better known in Germany under the brand name Ritalin. This amphetamine-like substance affects the metabolism of dopamine; it is designed to increase attention and perception and to reduce psychomotor activity and impulsiveness.

When administered to the zebrafish larvae, methylphenidate demonstrated similar results: the larvae did not swim anywhere near the distances that they had been covering before. Their speed also reduced considerably – to that of “normal”, untreated larvae.

The authors draw two consequences from the results of this study: firstly, the findings clearly show the importance of the lphn3 gene to the development of the dopaminergic signaling pathway in the embryonic phase. Secondly, they demonstrate that reduced lphn3 functionality in zebrafish larvae causes typical changes in behavior that are very similar to the usual characteristics of ADHD.

About ADHD

According to the latest estimates, between three and seven percent of all children suffer from attention deficit hyperactivity disorder (ADHD). Boys are around four times more likely to be affected than girls. Contrary to popular belief, adults can also suffer from ADHD; around four percent apparently show typical symptoms.

Those affected are usually hyperactive and possess an increased urge to move, they tend to be more impulsive, and they find it hard to concentrate. For this reason, children and young people often experience difficulties in education and training; adult sufferers frequently have problems in their careers and relationships.

The genetic component in the development of ADHD is estimated at 70 to 80 percent. But environmental influences can also mitigate or exacerbate the symptoms. Cigarettes and alcohol during pregnancy increase the risk, as does a premature birth or a low birth weight.

The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development; M Lange, W Norton, M Coolen, M Chaminade, S Merker, F Proft, A Schmitt, P Vernier, K-P Lesch and L Bally-Cuif. Molecular Psychiatry 2012, 17:946-54, doi:10.1038/mp.2012.29.

Contact

Prof. Dr. Klaus-Peter Lesch,
T: +49 (0)931 201-77600, e-mail: kplesch@mail.uni-wuerzburg.de