Drug alleviates autism-associated behavior in mice

Disorders from the autism spectrum (ASD, autism spectrum disorders) are not only manifested by impairments in social interaction, communication, interest formation and by stereotypical behavior patterns, but are often accompanied by other phenotypes such as epilepsy or hyperactivity.

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

Moritz Mall from the Hector Institute for Translational Brain Research (HITBR) has long been researching the role of the protein MYT1L in various neuronal diseases. The protein is a so-called 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 entire life span.

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

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

What was particularly striking about the MYT1L-deficient neurons: They produced an excess of a sodium channels that are normally mainly restricted to the heart muscle cells. These pore-shaped proteins allow sodium ions to pass through the cell membrane and are thus crucial for 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.

In clinical medicine, 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 curb ASD-associated behaviors such as hyperactivity.

"Apparently, drug treatment in adulthood can alleviate brain cell dysfunction and thus counteract the behavioral abnormalities in MYT1L mutant mice - 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 in mice; clinical studies in MYT1L patients with disorders from the ASD spectrum have not yet been conducted. 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 established by the Central Institute of Mental Health (ZI), the German Cancer Research Center (DKFZ) and the Hector Foundation II. The aim of HITBR is to identify new molecular and functional targets for the therapy of severe psychiatric diseases and brain tumors.