Abstract
AbstractPentylenetetrazole (PTZ) has recently been found to ameliorate cognitive impairment in rodent models of Down syndrome (DS). The mechanism underlying PTZ’s therapeutic effect is however not clear. Microarray profiling has previously reported differential expression of genes in DS. No mammalian transcriptomic data on PTZ treatment however exists. Nevertheless, a Drosophila model inspired by rodent models of PTZ induced kindling plasticity has recently been described. Microarray profiling has shown PTZ’s downregulatory effect on gene expression in fly heads. In a comparative transcriptomics approach, I have analyzed the available microarray data in order to identify potential mechanism of PTZ action in DS. I find that transcriptomic correlates of chronic PTZ in Drosophila and DS counteract each other. A significant enrichment is observed between PTZ downregulated and DS upregulated genes, and a significant depletion between PTZ downregulated and DS dowwnregulated genes. Further, the common genes in PTZ downregulated and DS upregulated sets show enrichment for MAP kinase pathway. My analysis suggests that downregulation of MAP kinase pathway may mediate therapeutic effect of PTZ in DS. Existing evidence implicating MAP kinase pathway in DS supports this observation.
Highlights
Chronic treatment with nonconvulsive dosage of PTZ has recently been found to ameliorate cognitive impairment in rodent models of Down syndrome (DS) [1, 2, 3, 4]
I predicted that significant overlap between PTZ downregulated and DS upregulated genes may result from counteracting effect on MAP kinase signaling
The present functional genomic analysis suggests that potential therapeutic effect of PTZ in DS may be mediated by downregulation of MAP kinase signaling pathway
Summary
Chronic treatment with nonconvulsive dosage of PTZ has recently been found to ameliorate cognitive impairment in rodent models of DS [1, 2, 3, 4]. The mechanism underlying PTZ’s potential therapeutic effect in DS is unclear. Genome scale expression analysis offers a promising approach to identify genes and pathways relevant in pathophysiological and therapeutic mechanisms in complex CNS disorders [5]. Microarray gene expression profiling has previously been reported in the analysis of control versus DS astrocyte cell line and cerebrum or apical frontal pole [6], prefrontal cortex [7], and neural progenitor cells [8]. Transcriptomic analysis of PTZ treatment effect in mammalian system has not been undertaken yet. This precludes understanding drug’s potential mechanism using functional genomic data
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