Transcriptome bioinformatic analysis identifies potential therapeutic mechanism of pentylenetetrazole in down syndrome

In a comparative transcriptomics approach, I have analyzed the available microarray data in order to identify potential therapeutic mechanism of PTZ in DS. In the analysis, summary data of up- and down-regulated genes reported in human DS studies and of down-regulated genes reported in the Drosophila model has been used.I find that transcriptomic correlate of chronic PTZ in Drosophila counteracts that of DS. Genes downregulated by PTZ significantly over-represent genes upregulated in DS and under-represent genes downregulated in DS. Further, the genes which are common in the downregulated and upregulated DS set 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.Chronic treatment with nonconvulsive dosage of PTZ has recently been found to ameliorate cognitive impairment in rodent models of DS [1-4]. The mechanism underlying PTZ's potential therapeutic effect in DS is however 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]. However, transcriptomic analysis of effect of PTZ in mammalian system has not been undertaken yet. This precludes understanding drug's potential mechanism using functional genomic data.A Drosophila model inspired by rodent models of chronic PTZ induced kindling plasticity has recently been developed [9]. In this model, PTZ causes a decreased speed in startle-induced climbing in flies. Antiepileptic drugs, used in treating epilepsy and other neurological and psychiatric disorders, suppress development of this behavioral de