Impaired macroglial development and axonal conductivity contributes to the neuropathology of DYRK1A‐related intellectual disability syndrome

DYRK1A haploinsufficiency alters the production of cortical astrocytes and oligodendrocyte progenitors during development, as well as defects in the white matter and in the propagation of action potential in the adult. Thus, therapies aim at improving myelination and axon conduction velocities could ameliorate the cognitive, social and language deficits in DYRK1A syndrome.

Abstract

The correct development and activity of neurons and glial cells is necessary to establish proper brain connectivity. DYRK1A encodes a protein kinase involved in the neuropathology associated with Down syndrome that influences neurogenesis and the morphological differentiation of neurons. DYRK1A loss-of-function mutations in heterozygosity cause a well-recognizable syndrome of intellectual disability and autism spectrum disorder. In this study, we analysed the developmental trajectories of macroglial cells and the properties of the corpus callosum, the major white matter tract of the brain, in Dyrk1a^+/- mice, a mouse model that recapitulates the main neurological features of DYRK1A syndrome.  We found that Dyrk1a^+/- haploinsufficient mutants present an increase in astrogliogenesis in the neocortex and a delay in the production of cortical oligodendrocyte progenitor cells and their progression along the oligodendroglial lineage. There were fewer myelinated axons in the corpus callosum of Dyrk1a^+/- mice, axons that are thinner and with abnormal nodes of Ranvier. Moreover, action potential propagation along myelinated and unmyelinated callosal axons was slower in Dyrk1a^+/- mutants.  All these alterations are likely to affect neuronal circuit development and alter network synchronicity, influencing higher brain functions. These alterations highlight the relevance of glial cell abnormalities in neurodevelopmental disorders.

Reference:

Pijuan I, Balducci E, Soto-Sánchez C, Fernández E, Barallobre MJ, Arbonés ML. Impaired macroglial development and axonal conductivity contributes to the neuropathology of DYRK1A-related intellectual disability syndrome. Sci Rep. 2022 Nov 19;12(1):19912. doi: 10.1038/s41598-022-24284-5