Lamotrigine, a drug sold under the brand name Lamictal and used to treat epilepsy and to stabilize mood in bipolar disorder, stops behaviors associated with autism, such as hyperactivity.
The behavioral disturbances observed in autism are associated with a multitude of genetic alterations. Now, scientists at the Hector Institute for Translational Brain Research (HITBR) have found another molecular cause for this condition.
The MYT1L transcription factor normally protects the molecular identity of nerve cells. If it is genetically switched off, functional changes occur and symptoms typical of autism appear.
In the new study, recently published in Molecular Pyschiatryresearchers found that lamotrigine – a drug that blocks sodium channels in the cell membrane – can reverse the consequences of MYT1L failure and alleviate functional and behavioral abnormalities in mice.
Autism spectrum disorders do not only manifest themselves in problems with social interaction, communication, interest formation, and in stereotyped patterns of behavior. These factors are often accompanied by other conditions, such as epilepsy or hyperactivity.
Experts are trying to identify the molecular anomalies that contribute to this complex developmental disorder. A multitude of genetic factors that influence the molecular programs of nerve cells have been linked to the development of autism.
Moritz Mall, from HITBR, has long investigated the role of the MYT1L protein in various neurological diseases. The protein is a transcription factor that decides which genes are active in the cell and which are not. Almost all nerve cells in the body produce MYT1L throughout their life cycle.
The researcher had already demonstrated, a few years ago, that MYT1L protects the identity of nerve cells, suppressing other developmental pathways that program a cell towards muscle or connective tissue, for example. Were found MYT1L mutations in various neurological diseasessuch as schizophrenia and epilepsy, but also brain malformations.
In their current work, Mall and his team examined the exact role of the “guardian of neuronal identity” in the development of autism spectrum disorders. To do so, they genetically turned off MYT1L – both in mice and in human nerve cells derived from stem cells reprogrammed in the laboratory.
MYT1L loss led to electrophysiological hyperactivation in rat and human neurons, thereby impairing nerve function. Mice lacking MYT1L suffered brain anomalies, such as a thinner cerebral cortex. The animals also showed various behavioral changes typical of autism spectrum disorders, such as social deficits or hyperactivity.
What was particularly striking about the MYT1L-deficient neurons was that they produced an excess of sodium channels that are normally restricted to heart muscle cells.
These proteins allow the passage of sodium ions across the cell membrane, being crucial for electrical conductivity and therefore for the functioning of cells. If a nerve cell makes too many of these proteins, it can result in electrophysiological hyperactivation.
Drugs that block sodium channels have been used for a long time. These include the agent lamotrigine, which is supposed to prevent epileptic seizures. When MYT1L-deficient nerve cells were treated with lamotrigine, their electrophysiological activity returned to normal. In mice, the drug was even able to halt behaviors associated with autism spectrum disorders.
“Apparently, drug treatment in adulthood can alleviate brain cell dysfunction and counteract behavioral abnormalities typical of autism – even after the absence of MYT1L has already impaired brain development during the developmental phase of the organism,” explained Moritz Mall.
However, the results are limited to studies in mice – no clinical studies have yet been conducted in patients with autism spectrum disorders. The first clinical studies are in the early planning stages.
ZAP // 
