Interneuron migration defects during corticogenesis contribute toDyrk1ahaploinsufficiency syndrome pathogenesis via actomyosin dynamics deregulations

Abstract

ABSTRACTInterneuron 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 theDYRK1A-haploinsufficiency syndrome, caused by mutations ofDYRK1A, 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 thatDyrk1aspecifically 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 ofDyrk1ain interneurons show behavioral defects and epileptic activity, recapitulating phenotypes observed in human patients. Altogether, these data highlight the critical role ofDyrk1ain the development of the GABAergic system and the pathophysiology ofDYRK1A-haploinsufficiency syndrome.