MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention.

Scientists studied a gene called MYT1L that's linked to autism. When this gene doesn't work properly, it causes brain development problems and autism-like behaviors in mice. The researchers found that the gene problems lead to overactive brain cells. The good news is they discovered that a medication called lamotrigine could help fix these brain activity problems and improve behaviors, suggesting potential treatment options.

This study investigated how mutations in MYT1L, a gene associated with autism spectrum disorder, affect brain development and function. Researchers used both human neurons and mouse models to examine MYT1L deficiency. They found that MYT1L mutations cause developmental delays, thinner brain cortices, autism-like behaviors, and altered gene expression patterns. The study identified that MYT1L deficiency leads to overactivation of WNT and NOTCH signaling pathways and upregulation of SCN5A sodium channels, causing neuronal hyperactivity.

Importantly, the researchers demonstrated that these defects could be rescued through genetic interventions and pharmacological treatment with lamotrigine, a sodium channel blocker, which normalized both brain activity and behavioral phenotypes.

This research suggests that some autism-related symptoms caused by MYT1L mutations might be treatable with existing medications like lamotrigine. The findings indicate that even developmental genetic causes of autism may have reversible components, opening new therapeutic possibilities for precision medicine approaches in autism treatment.

Study type and sample sizes are not reported in the abstract. Research conducted in mouse models and human neurons in laboratory settings may not fully translate to clinical populations. Long-term safety and efficacy of lamotrigine intervention in humans with MYT1L mutations remains unknown.

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 enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients.

MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1L mutation causes both developmental and postmitotic neurological defects.

However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.