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Molecular Psychiatry

Molecular Psychiatry

IF: 9.6
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MYT1L haploinsufficiency in human neurons and mice causes autism-associated phenotypes that can be reversed by genetic and pharmacologic intervention

Published:14 February 2023 DOI: 10.1038/s41380-023-01959-7 PMID: 36782060
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

Abstract

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.

Substances (6)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Lamotrigine 84057-84-1 C9H7Cl2N5 680 suppliers $5.00-$1720.00
Lamotrigine 84057-84-1 C9H7Cl2N5 680 suppliers $5.00-$1720.00
Lamotrigine 84057-84-1 C9H7Cl2N5 680 suppliers $5.00-$1720.00
Lamotrigine 84057-84-1 C9H7Cl2N5 680 suppliers $5.00-$1720.00
Lamotrigine 84057-84-1 C9H7Cl2N5 - Inquiry
Lamotrigine 84057-84-1 C9H7Cl2N5 - Inquiry

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