How much do you know about the effects of glutamate on the frontostriatal circuits? Not as much as you'd like, possibly, but then again there is still a lot to learn. EU-funded researchers are studying the role of this neurotransmitter and potential genetic factors in the development of compulsive disorders such as autism, ADHD and OCD.
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The Tactics programme strives to identify the genetic and neural underpinnings of compulsivity in children and adolescents, and explore new possibilities for treatment,” says project coordinator Jan Buitelaar of Radboud University Medical Centre in Nijmegen, Netherlands. The research focuses on three types of illness: autism spectrum disorders, obsessive-compulsive disorders (OCDs), and conditions linked to impulse control, which notably include attention-deficit hyperactive disorder (ADHD).
More specifically, Tactics is investigating suspected links with the brain’s production and processing of glutamate and analysing possible genetic risk factors. It is also establishing whether a glutamate-modulating drug currently used to treat Alzheimer’s disease could be of help.
Halfway into the four-year project, the partners have already reported exciting results. Their findings indicate that young patients’ inability to pursue long-term rewards may be linked with an overactive glutamate system, Buitelaar explains. However, he says, this mechanism is not apparent in adults struggling with impulse control, whose brain scans actually tend to reveal lower glutamate signals.
In addition, the team has spotted a potential connection between compulsivity and insulin. Central to glucose control and the body’s energy metabolism, this hormone also appears to contribute to the functioning of the brain.
Compulsive disorders can be brought on by a number of causes. Genetic predisposition is one of them, says Buitelaar, but this is unlikely to originate in a single gene. It is more a case of “genetic landscapes” conducive to compulsivity, he explains, i.e. hundreds of genes presenting specificities that jointly increase the risk.
There are many different types of compulsive disorder, characterised by symptoms as diverse as relentless cleaning, a persistent inability to sit still, or uncontrollable gambling. The myriad of genes involved may jointly shape physiological processes that could be targeted with drugs, Buitelaar explains.
The partners are also generating new knowledge about the neural wiring linked to compulsivity. Their attention focuses particularly on the frontostriatal cortex, the connection between the frontal lobes of the brain and the so-called basal ganglia, which are notably involved in repetitive and reward-related behaviours.
“We think that the frontostriatal circuits are not functioning well in children with clinical symptoms of compulsivity,” says Buitelaar. “We are investigating the effects of glutamate, one of the more powerful neurotransmitter systems modulating the activity of these circuits.”
“In particular,” he adds, “we are exploring whether interventions in the glutamate system can influence their function.” Research on mice and rats has led Tactics to conclude that this approach does indeed show promise if the compulsivity problem expresses itself in a reward-related disorder.
This finding was not unexpected, Buitelaar notes, but the realisation that insulin may also play a role in compulsivity came as a surprise. In fact, he adds, this role may be even greater than that of glutamate.
A need to succeed
“We focus on children between 8 and 12 because there are a lot of changes in brain function and structure at that age,” Buitelaar explains. “This stage is also the beginning of puberty, where risk increases for reward-related substance abuse or addictive behaviours.”
Breakthroughs in identifying kids that might be prone to compulsive disorders such as these could thus help to keep them healthy as they grow up. It would also greatly reduce the prospective burden on their families and on society. Compulsivity can come at a great cost to the patient and to the wider world — for example in cases where the disorder limits a person’s ability to refrain from harmful behaviour.
There is still a long way to go, but promising leads have begun to emerge. “Research brings us closer to the real mechanisms, and so closer to potential treatments,” Buitelaar concludes.