summary: A newly developed drug that blocks plasma membrane sodium channels that can reverse MYT1L impairment attenuates social behavior deficits in a mouse model of ASD.
sauce: German Cancer Research Center
The behavioral deficits observed in autism are associated with numerous genetic alterations. Scientists at the Hector Institute for Translational Brain Research (HITBR) have discovered another molecular cause of the condition.
The transcription factor MYT1L normally protects the molecular identity of neurons. When it is genetically switched off in human neurons and mice, functional alterations and symptoms typical of autism occur.
Agents that block plasma membrane sodium channels can reverse the consequences of MYT1L deficiency and alleviate functional and behavioral abnormalities in mice.
Autism spectrum disorders (ASD, Autism Spectrum Disorder) are manifested by impairments in social interaction, communication, interest formation, and stereotypical behavioral patterns, as well as other abnormalities such as epilepsy and hyperactivity. often accompanied by
Scientists are eagerly searching for molecular abnormalities that contribute to this complex developmental disorder. Numerous genetic factors that influence neuronal molecular programming have already been linked to the development of autism.
Moritz Mall at the Hector Institute for Translational Brain Research (HITBR) has long studied the role of the protein MYT1L in various neurological diseases. This protein is a so-called transcription factor that determines which genes in the cell are activated and which are not. Nearly every nerve cell in the body produces his MYT1L throughout life.
Mall had already shown several years ago that MYT1L protects neuronal identity, for example by repressing other developmental pathways that program cells towards muscle and connective tissue. , has been found in brain malformations as well as in several neurological disorders such as schizophrenia and epilepsy.
In a current study, Mohr and his team investigated the precise role of ‘guardians of neuronal identity’ in the development of ASD. To do this, we genetically turned off MYT1L in both mouse and human neurons derived from laboratory-reprogrammed stem cells.
Loss of MYT1L led to electrophysiological hyperactivation of neurons in mice and humans and impaired neuronal function. Mice lacking MYT1L suffered from brain abnormalities such as thinning of the cerebral cortex. Animals also exhibited behavioral changes typical of some ASS, such as social deficits and hyperactivity.
What was particularly striking was that MYT1L-deficient neurons produced excess sodium channels that are normally restricted primarily to cardiomyocytes. These pore-shaped proteins allow sodium ions to pass through the cell membrane and are therefore important for electrical conductivity and cell function. Hyperactivity may occur.
Drugs that block sodium channels have long been used in clinical medicine. These include the drug lamotrigine, which is thought to prevent epileptic seizures. Treatment of MYT1L-deficient neurons with lamotrigine restored electrophysiological activity to normal. In mice, the drug was even able to suppress ASD-related behaviors such as hyperactivity.
“Clearly, drug treatment in adulthood can reduce brain cell dysfunction and counteract the behavioral abnormalities typical of autism. is already compromised,” explains Moritz Mall.
However, the results are still limited to studies in mice. Clinical studies of patients with disorders of the ASD spectrum have not yet been conducted. The first clinical trials are in the early stages of planning.
ASD and neuropharmacology research news
author: press office
sauce: German Cancer Research Center
contact: Press Office – German Cancer Research Center
image: image is public domain
See also
Original research: open access.
“MYT1L haploinsufficiency in human neurons and mice causes an autism-associated phenotype that can be reversed by genetic and pharmacological interventionsby Bettina Weigel et al. molecular psychiatry
overview
MYT1L haploinsufficiency in human neurons and mice causes an autism-associated phenotype that can be reversed by genetic and pharmacological interventions
MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life.how MYT1L Mutations cause neurological phenotypes and whether they can be targeted remains a mystery.
Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice display neurodevelopmental delay with thinner cortices, behavioral phenotypes, and altered gene expression similar to those of ASD patients.
MYT1L target genes including WNTs and notch, are activated upon MYT1L depletion, and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of key cardiac sodium channels. SCN5Aand neuronal hyperactivity may be restored by shRNA-mediated knockdown SCN5A again MYT1L Overexpression in postmitotic neurons.
Acute application of the sodium channel blocker lamotrigine also rescued electrophysiological defects in vitro and behavioral phenotypes in vivo. therefore, MYT1L Mutations cause both developmental and post-mitotic neurological deficits.
However, acute intervention can normalize electrophysiological and behavioral phenotypes that occur in adulthood.
