Drug alleviates autism-associated behaviours in mice

Diseases from the autism spectrum (ASD, autism spectrum disorders) are not only characterised by impairments in social interaction, communication, interest formation and stereotypical behaviour patterns. This is often accompanied by other disorders in those affected, such as epilepsy or hyperactivity.

Scientists are intensively searching for the molecular abnormalities that contribute to this complex developmental disorder. A large number of genetic factors that influence the molecular programmes of nerve cells have already been linked to the development of autism.

Moritz Mall from the Hector Institute for Translational Brain Research (HITBR) has been researching the role of the MYT1L protein in various neuronal diseases for a long time. The protein is a so-called transcription factor that determines which genes are transcribed in the cell and which are not. Almost all nerve cells in the body produce MYT1L throughout their entire lifespan.

Mall had already shown several years ago that MYT1L protects the identity of nerve cells by suppressing other developmental programmes that programme a cell towards muscle or connective tissue, for example. Mutations in MYT1L have been found in several neurological diseases, such as schizophrenia and epilepsy, but also in malformations of the brain. In their current work, which is funded by the European Research Council ERC, Mall and his team are investigating the exact role played by the "guardian of neuronal identity" in the development of ASD. To do this, they genetically switched off MYT1L - both in mice and in human nerve cells that had been obtained in the laboratory from reprogrammed stem cells.

The loss of MYT1L led to electrophysiological hyperactivation in mouse and human nerve cells and thus impaired nerve function. Mice lacking MYT1L exhibited brain abnormalities, such as a thinner cerebral cortex. The animals also showed several behavioural changes typical of ASD, such as social deficits or hyperactivity.

In the MYT1L-deficient neurones, it was particularly noticeable that they produced a sodium channel in the periphery, which is normally mainly formed by heart muscle cells. These porous proteins allow sodium ions to pass through the cell membrane and are therefore crucial for the electrical conductivity and thus also for the functioning of the cells. If a nerve cell produces too many of these channel proteins, electrophysiological hyperactivation can be the result.

Medications that block sodium channels have been used in medicine for a long time. These include the active ingredient lamotrigine, which is intended 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 curb ASA-associated behavioural patterns such as hyperactivity.

„Apparently, drug treatment in adulthood can alleviate the malfunctions of the brain cells and thus counteract the behavioural problems typical of autism– even after the absence of MYT1L has already impaired brain development during the developmental phase of the organism," explains Moritz Mall. However, the results are still limited to studies on mice; clinical studies on patients with diseases from the ASD spectrum are not yet available. The first clinical studies are in the early planning phase.

Bettina Weigel, Jana F. Tegethoff, Sarah D. Grieder, Bryce Lim, Bhuvaneswari Nagarajan, Yu-Chao Liu, Jule Truberg, Dimitris Papageorgiou, Juan M. Adrian-Segarra, Laura K. Schmidt, Janina Kaspar, Eric Poisel, Elisa Heinzelmann, Manu Saraswat, Marleen Christ, Christian Arnold, Ignacio L. Ibarra, Joaquin Campos, Jeroen Krijgsveld, Hannah Monyer, Judith B. Zaugg, Claudio Acuna and Moritz Mall: MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention

Molecular Psychiatry; 2023, https://doi.org/10.1038/s41380-023-01959-7

* The Hector Institute for Translational Brain Research (HITBR) is a joint institution of the Central Institute of Mental Health (ZI), the German Cancer Research Centre (DKFZ) and the Hector Foundation II. The aim of HITBR is to identify new molecular and functional targets for the treatment of severe psychiatric disorders and brain tumours.

Notification of the "German Cancer Research Centre in the Helmholtz Association" from 14.02.2023