Autism spectrum disorders are early onset neurodevelopmental disorders characterized by deficits in social communication and restricted repetitive behaviors, yet they are quite heterogeneous in terms of their genetic basis and phenotypic manifestations. Recently, de novo pathogenic mutations in DYRK1A, a chromosome 21 gene associated to neuropathological traits of Down syndrome, have been identified in patients presenting a recognizable syndrome included in the autism spectrum. These mutations produce DYRK1A kinases with partial or complete absence of the catalytic domain, or they represent missense mutations located within this domain. Here, we undertook an extensive biochemical characterization of the DYRK1A missense mutations reported to date and show that most of them, but not all, result in enzymatically dead DYRK1A proteins. We also show that haploinsufficient Dyrk1a+/- mutant mice mirror the neurological traits associated with the human pathology, such as defective social interactions, stereotypic behaviors and epileptic activity. These mutant mice present altered proportions of excitatory and inhibitory neocortical neurons and synapses. Moreover, we provide evidence that alterations in the production of cortical excitatory neurons are contributing to these defects. Indeed, by the end of the neurogenic period, the expression of developmental regulated genes involved in neuron differentiation and/or activity is altered. Therefore, our data indicate that altered neocortical neurogenesis could critically affect the formation of cortical circuits, thereby contributing to the neuropathological changes in DYRK1A haploinsufficiency syndrome.

This work was supported by grants from the Spanish Ministry of Economia, Industria y Competitividad (MINECO) (BFU2016-81887-REDT, SAF2013-46676-P and SAF2016-77971-R to M.L.A. and BFU2013-44513 and BFU2016-76141 to S.L.), the Secretariat of Universities and Research-Generalitat de Catalunya (2014SGR674), and the Fundación Alicia Koplowitz (Spain). The group of S.L. acknowledges the support of the MINECO Centro de Excelencia Severo Ochoa Programme and of the CERCA Programme (Generalitat de Catalunya). G.S-E. and M.P.S. acknowledge the support of the National Institute of Neurological Disorders and Stroke of the National Institutes of Health(USA) (P01NS097197) and the Spanish Instituto de Salud Carlos III (ISCIII), (PI13/00865, Fondo Europeo de Desarrollo Regional -FEDER “A way of making Europe”, Spain). M.J.B. is supported by the CIBERER, an initiative of the ISCIII. J.A., E.B. and S.N. were supported by MINECO predoctoral fellowships (AP2012-3064 and BES2011-047472) and G.S-E. by a predoctoral fellowship from the Fundación Conchita Rábago, Spain.