Increased NR2A expression and prolonged decay of NMDA-induced calcium transient in cerebellum of TgDyrk1A mice, a mouse model of Down syndrome

• Published in: Neurobiology of disease Vol. 32; no. 3; pp. 377 - 384
• Main Authors: Altafaj, X, Ortiz-Abalia, J, Fernández, M, Potier, M.C, Laffaire, J, Andreu, N, Dierssen, M, González-García, C, Ceña, V, Martí, E, Fillat, C
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2008; Elsevier
• Subjects: Animals; Blotting, Western; Calcium - metabolism; Cells, Cultured; Cerebellum; Cerebellum - metabolism; Disease Models, Animal; Down syndrome; Down Syndrome - genetics; Down Syndrome - metabolism; Dyrk Kinases; DYRK1A; Gene Expression Profiling; Immunohistochemistry; In Vitro Techniques; Male; Mice; Mice, Transgenic; Microarrays; Motor phenotype; Murine models; N-Methylaspartate - pharmacology; Neurology; Neurons - metabolism; NMDA receptors; Oligonucleotide Array Sequence Analysis; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - physiology; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - physiology; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Synaptosomes - metabolism; Up-Regulation; Cerebellum; Motor phenotype; Murine models; Microarrays; DYRK1A; Down syndrome; NMDA receptors
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2008.07.024

Abstract Transgenic mice overexpressing Dyrk1A (TgDyrk1A), a Down syndrome (DS) candidate gene, exhibit motor and cognitive alterations similar to those observed in DS individuals. To gain new insights into the molecular consequences of Dyrk1A overexpression underlying TgDyrk1A and possibly DS motor phenotypes, microarray studies were performed. Transcriptome analysis showed an upregulation of the NR2A subunit of the NMDA type of glutamate receptors in TgDyrk1A cerebellum. NR2A protein overexpression was also detected in TgDyrk1A cerebellar homogenates, in the synaptosome-enriched fraction and in TgDyrk1A primary cerebellar granular neuronal cultures (CGNs). In TgDyrk1A synaptosomes, calcium-imaging experiments showed a higher calcium uptake after NMDA stimulation. Similarly, NMDA administration promoted longer calcium transients in TgDyrk1A CGNs. Taken together, these results show that NMDA-induced calcium rise is altered in TgDyrk1A cerebellar neurons and indicate that calcium signaling is dysregulated in TgDyrk1A mice cerebella. These findings suggest that DYRK1A overexpression might contribute to the dysbalance in the excitatory transmission found in the cerebellum of DS individuals and DS mouse models.