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

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.

Automated summary

MYT1L, a transcription factor associated with autism spectrum disorder (ASD), is expressed in all neurons and its mutation causes neurodevelopmental delays, behavioral phenotypes, and gene expression changes resembling ASD patients. MYT1L depletion activates target genes WNT and NOTCH, while their chemical inhibition rescues delayed neurogenesis. MYT1L deficiency upregulates cardiac sodium channel SCN5A and neuronal hyperactivity, which can be restored by knockdown of SCN5A or MYT1L overexpression. Acute application of sodium channel blocker lamotrigine rescues electrophysiological and behavioral defects. Therefore, MYT1L mutation causes both developmental and postmitotic neurological defects, but acute intervention can normalize these phenotypes in adulthood.