期刊
NEUROBIOLOGY OF DISEASE
卷 127, 期 -, 页码 210-222出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2019.02.022
关键词
Autism spectrum disorder; Cerebral cortex; DYRK1A mutations; Epilepsy; Neurodevelopment; Transcriptome
资金
- Spanish Ministry of Economia, Industria y Competitividad (MINECO) [BFU2016-81887-REDT, SAF2013-46676-P, SAF2016-77971-R, BFU2013-44513, BFU2016-76141]
- Secretariat of Universities and Research-Generalitat de Catalunya [2014SGR674]
- Fundacion Alicia Koplowitz (Spain)
- MINECO Centro de Excelencia Severo Ochoa Programme
- CERCA Programme (Generalitat de Catalunya)
- National Institute of Neurological Disorders and Stroke of the National Institutes of Health (USA) [P01NS097197]
- Spanish Instituto de Salud Carlos III (ISCIII), Spain [PI13/00865]
- CIBERER, an initiative of the ISCIII
- MINECO predoctoral fellowships [AP2012-3064, BES2011-047472]
- Fundacion Conchita Rabago, Spain
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 haploinsufficientDyrkla(+/-) 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.
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