Interneuron migration defects during corticogenesis contribute to Dyrk1a haploinsufficiency syndrome pathogenesis via actomyosin dynamics deregulations
Résumé
ABSTRACT Interneuron development is a crucial step of brain corticogenesis. When affected it often leads to brain dysfunctions, such as epilepsy, intellectual disabilities and autism spectrum disorder. Such defects are observed in the DYRK1A -haploinsufficiency syndrome, caused by mutations of DYRK1A , and commonly associated to cortical excitatory/inhibitory imbalance. However, how this imbalance is established in this syndrome remains elusive. Here, using mouse models and live imaging, we show that Dyrk1a specifically regulates the development of the cortical GABAergic system. Unlike projection excitatory neurons, we demonstrate that interneuron tangential migration relies on Dyrk1a dosage and kinase activity through a mechanism involving actomyosin cytoskeleton remodeling. Interestingly, we further demonstrate that mice with heterozygous inactivation of Dyrk1a in interneurons show behavioral defects and epileptic activity, recapitulating phenotypes observed in human patients. Altogether, these data highlight the critical role of Dyrk1a in the development of the GABAergic system and the pathophysiology of DYRK1A -haploinsufficiency syndrome.