Drug Alleviates Autism-Associated Behavior

The behavioral disorders observed in autism are associated with a multitude of genetic alterations. Scientists from the Hector Institute for Translational Brain Research (HITBR) have now found another molecular cause for this condition. The transcription factor MYT1L normally protects the molecular identity of nerve cells. 

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. This is often accompanied by other abnormalities such as epilepsy or hyperactivity.

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.

Mutations in MYT1L have been found in several neurological diseases, such as schizophrenia and epilepsy, but also in brain malformations. In their current work, 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. The animals also showed several ASS-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. 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 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 in mice; clinical studies in patients with disorders from the ASD spectrum have not yet been conducted. 

Sources:

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, 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; DOI: 10.1038/s41380-023-01959-7

German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). “Drug alleviates autism-associated behavior in mice.” ScienceDaily. ScienceDaily, 14 February 2023. <www.sciencedaily.com/releases/2023/02/230213201102.htm>.

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