Studying the dysregulation of expression of glutamate receptors is crucial to better understand the mechanisms associated with cognitive disabilities in Down syndrome (DS) patients. By using data of microarray experiments previously deposited in GEO Dataset, we studied the expression of 26 glutamate receptor genes in DS brain samples since prenatal to adult age in several brain structures. Overall, our results showed a complexity in the expression of the genes which were dependent mainly on the brain structure analyzed; especially, the hippocampus showed a different expression pattern. While in the general brain analysis the overexpressed genes were GRIN3A and GRIN2C, higher expression levels of GRM1, GRID2, and GRIK1 gene receptors were recorded in hippocampus. Our results suggest that the glutamatergic system in association with other neurotransmitter systems in the human brain would associate with glutamatergic receptor alterations to bring upon synaptic changes and cognitive deficits in DS models.
Background: Although Down syndrome (DS) is a trisomy of chromosome 21 being the most frequent human chromosomal disorder mainly associated with variable levels of intellectual disability and other dysfunctions, the only dose disbalance effect would not enough to explain its genetic and functional complexity neurophenotype. In this context, we aimed to analyze and compare the disruption of transcriptome of several brain areas from individuals with DS and euploid controls as a new approach to consider a global systemic differential disruption of gene expression beyond of chromosome 21. Methodology: To perform the analysis carried out in the present study, we used data from a DNA microarray experiment with ID GSE59630 previously deposited in the GEO DataSet of NCBI database. The array contained log2 values of 17,537 human genes expressed in several aeras of human brain. The data was collected from 58 postmortem brain samples of individuals with DS and 58 samples from euploid controls. We calculated the differential gene expression (Z-ratio) of all genes from the microarray according to the several brain areas, gene distribution per chromosome and age ranks. Results: We found several differences in gene expression along the DS brain transcriptome, not only in the genes located at chromosome 21 but in other chromosomes. Moreover, we registered the lowest Z-ratio correlation between the age ranks of 16-22 weeks of gestation and 39-42 years (R2=0.06) and the highest Z-ratio correlation between the age ranks of 30-39 years and 40-42 years (R2=0.89). The analysis per brain areas showed that the hippocampus and the cerebellar cortex had the most different gene expression pattern when compared to the brain as a whole. Conclusions: Our results revealed the complexity of gene expression networks in the transcriptome profiles of hippocampus, dorsolateral prefrontal cortex (DFC) and cerebellar cortex (CBC). Moreover, our approach opens a new vision of the genomic complexity of DS as a pathology of multiple and complex variables that are playing altogether to modeling their pathogenesis.
ResumenUno de los retos más importantes de este siglo en la neurología genómica es construir mapas de expresión espacial de genes a lo largo de las distintas estructuras cerebrales con el fin de correlacionarlos con ciertas neuropatologías. Se analizaron los perfiles de transcripción de ocho genes HAS21 localizados en la región crítica del síndrome de Down en diferentes estructuras del cerebro humano normal. Se tomaron como referencia los valores de expresión de ocho genes HAS21/DSCR provenientes de experimentos de micromatrices de ADN de cerebros humanos normales y cuyos valores están disponibles en la base de datos del proyecto cerebro humano del Atlas del Cerebro del Allen Institute for Brain Sciences en Seattle, Washington (http://www.brain-map.org). Se determinó una expresión diferencial de estos genes HAS21/DSCR a lo largo de las estructuras localizadas en el lóbulo frontal, el lóbulo límbico y en los núcleos centrales. En el putamen, el núcleo caudado, el giro parahipocampal y en las áreas centrales se registraron los mayores niveles de transcripción global; estas áreas del cerebro parecen estar asociadas con diversos procesos de aprendizaje y de memoria. Se correlacionó la transcripción diferencial de genes DSCR con la localización cerebral y su potencial papel funcional.Palabras claves: Análisis de micromatrices, perfilación de la expresión génica, biología computacional, cerebro, síndrome de Down. IN SILICO SYSTEMIC ANALYSIS OF THE DIFFERENTIAL EXPRESSION OF GENES LOCALIZED IN THE DOWN SYNDROME CRITICAL REGION (DSCR) IN NORMAL HUMAN BRAIN AbstractOne of the most important challenges of the 21st Century Neurology is to build gene expression profiles along the different structures of human brain trying to correlate them with some neuropathologies. The expression profiles of eight HAS21 genes located on the Down syndrome critical region
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