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Neurobiol Dis. 2019 Jul;127:210-222. doi: 10.1016/j.nbd.2019.02.022. Epub 2019 Mar 1.

Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome.

Author information

1
Instituto de Biología Molecular de Barcelona (IBMB), CSIC, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
2
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology (BIST), 08003 Barcelona, Spain.
3
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain; Department of Neuroscience, Laboratory of Neurology, IIS-Jiménez Díaz Foundation, 28040 Madrid, Spain.
4
Instituto de Biología Molecular de Barcelona (IBMB), CSIC, 08028 Barcelona, Spain.
5
Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa (CBMSO), CSIC/UAM, 28049 Madrid, Spain.
6
Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology (BIST), 08003 Barcelona, Spain.
7
PCB-PRBB Animal Facility Alliance, 08020 Barcelona, Spain.
8
Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa (CBMSO), CSIC/UAM, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
9
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain; Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology (BIST), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Electronic address: susana.luna@crg.eu.
10
Instituto de Biología Molecular de Barcelona (IBMB), CSIC, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. Electronic address: marbmc@ibmb.csic.es.

Abstract

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.

KEYWORDS:

Autism spectrum disorder; Cerebral cortex; DYRK1A mutations; Epilepsy; Neurodevelopment; Transcriptome

PMID:
30831192
PMCID:
PMC6753933
[Available on 2020-07-01]
DOI:
10.1016/j.nbd.2019.02.022
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