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A Drosophila systems model of pentylenetetrazole induced locomotor plasticity responsive to antiepileptic drugs.

Mohammad F, Singh P, Sharma A - BMC Syst Biol (2009)

Bottom Line: Pathway overrepresentation analysis showed enrichment of Wnt signaling and other associated pathways in genes downregulated by PTZ.Mining of available transcriptomic and proteomic data pertaining to established rodent models of epilepsy and human epileptic patients showed overrepresentation of epilepsy associated genes in our PTZ regulated set.Amenable to modeling, our model offers a unique opportunity to further dissect epileptogenesis-like plasticity and to unravel mechanisms of long-term action of AEDs relevant in neuropsychiatric disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Genomics and Integrative Biology, Delhi University Campus, India.

ABSTRACT

Background: Rodent kindling induced by PTZ is a widely used model of epileptogenesis and AED testing. Overlapping pathophysiological mechanisms may underlie epileptogenesis and other neuropsychiatric conditions. Besides epilepsy, AEDs are widely used in treating various neuropsychiatric disorders. Mechanisms of AEDs' long term action in these disorders are poorly understood. We describe here a Drosophila systems model of PTZ induced locomotor plasticity that is responsive to AEDs.

Results: We empirically determined a regime in which seven days of PTZ treatment and seven days of subsequent PTZ discontinuation respectively cause a decrease and an increase in climbing speed of Drosophila adults. Concomitant treatment with NaVP and LEV, not ETH, GBP and VGB, suppressed the development of locomotor deficit at the end of chronic PTZ phase. Concomitant LEV also ameliorated locomotor alteration that develops after PTZ withdrawal. Time series of microarray expression profiles of heads of flies treated with PTZ for 12 hrs (beginning phase), two days (latent phase) and seven days (behaviorally expressive phase) showed only down-, not up-, regulation of genes; expression of 23, 2439 and 265 genes were downregulated, in that order. GO biological process enrichment analysis showed downregulation of transcription, neuron morphogenesis during differentiation, synaptic transmission, regulation of neurotransmitter levels, neurogenesis, axonogenesis, protein modification, axon guidance, actin filament organization etc. in the latent phase and of glutamate metabolism, cell communication etc. in the expressive phase. Proteomic interactome based analysis provided further directionality to these events. Pathway overrepresentation analysis showed enrichment of Wnt signaling and other associated pathways in genes downregulated by PTZ. Mining of available transcriptomic and proteomic data pertaining to established rodent models of epilepsy and human epileptic patients showed overrepresentation of epilepsy associated genes in our PTZ regulated set.

Conclusion: Systems biology ultimately aims at delineating and comprehending the functioning of complex biological systems in such details that predictive models of human diseases could be developed. Due to immense complexity of higher organisms, systems biology approaches are however currently focused on simpler organisms. Amenable to modeling, our model offers a unique opportunity to further dissect epileptogenesis-like plasticity and to unravel mechanisms of long-term action of AEDs relevant in neuropsychiatric disorders.

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Overinteraction of CG7583 (CtBP). Interacting partners of CG7583 in the network of self-interacting PTZ regulated genes are shown. For details, see text.
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Figure 5: Overinteraction of CG7583 (CtBP). Interacting partners of CG7583 in the network of self-interacting PTZ regulated genes are shown. For details, see text.

Mentions: For providing direction to the transcriptomic changes, we first overlaid all 2574 genes present in 12 hrs, 2nd day and 7th day sets onto protein interactome map of D. melanogaster (interaction database BioGRID v 2.0, visualization software platform Osprey v. 1.2.0, ) which consisted of 7358 genes (vertices) and 24984 connections (edges) [47]. Out of 2574 PTZ regulated genes, 1633 were present in the fly interactome. We retrieved PTZ gene specific subinteractome that consisted of 1633 vertices and 1485 edges. In this subinteractome map, 632 genes were found to be loner, i.e., they did not show any within group interaction. We hereafter focused on within group interaction network which was comprised of 1001 genes and 1485 interactions (for interacting genes, see additional file 5). We next examined which of the 12 hrs gene(s) shows statistically significant overinteraction in the network of 1001 vertices and 1485 edges. Among 13 beginning phase, i.e., 12 hrs, genes present in the network, only the C-terminal Binding Protein (CtBP, CG7583) was found to overinteract (hypergeometric distribution after Bonferroni correction, p = 0.004; Table 3; Figure 5). CG7583 and its direct interacting partners, a network comprising of 17 genes, showed overrepresentation of various GO processes which were mainly related to transcriptional regulation and cell fate determination (Table 4). Transcriptional alteration was thus identified as the most proximal effect of PTZ. To complete adding direction, we retrieved enriched processes in genes which showed interaction with interacting partners of CG7583 in the self-interacting network of our PTZ genes, and so on, till completion; of 1001 genes, 898 were consumed by this CG7583 centered network. Enrichment of cell morphogenesis and protein import into nucleus; neuron differentiation, neurogenesis, axonogenesis, axon guidance, small GTPase mediated signal transduction, actin filament organization, cell growth, transmembrane receptor protein tyrosine kinase signaling pathway, eye photoreceptor cell differentiation, regulation of cell shape and regulation of cell size; phospholipase C activation and positive regulation of hydrolase activity was observed, in that order (for complete lists of enriched GO processes, see additional file 6). Broadly, process enrichment analysis guided by protein interactome suggested that chronic PTZ sequentially downregulates transcription, neurogenesis/axonogenesis/axon guidance and phospholipase C activation. This was consistent with original time series analysis presented above (Tables 1 and 2), except that glutamate metabolism related processes enriched on 7th day (Table 2) were not recovered by interactome guided analysis. Seventh day genes under these categories – CG7145, CG5320 (Gdh), CG14994 (Gad1), CG1743 (Gs2) and CG8430 (Got1) – are poorly connected in the entire fly interactome (range, 0–3 interactions). It is likely that non-recovery of glutamate metabolism related processes reflect poor interaction of the genes involved. Cumulatively, the above results suggested that sequential downregulation of gene expression, neurogenesis/axonogenesis/axon guidance, phospholipase C activation and glutamate metabolism characterize our fly behavioral model.


A Drosophila systems model of pentylenetetrazole induced locomotor plasticity responsive to antiepileptic drugs.

Mohammad F, Singh P, Sharma A - BMC Syst Biol (2009)

Overinteraction of CG7583 (CtBP). Interacting partners of CG7583 in the network of self-interacting PTZ regulated genes are shown. For details, see text.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2657775&req=5

Figure 5: Overinteraction of CG7583 (CtBP). Interacting partners of CG7583 in the network of self-interacting PTZ regulated genes are shown. For details, see text.
Mentions: For providing direction to the transcriptomic changes, we first overlaid all 2574 genes present in 12 hrs, 2nd day and 7th day sets onto protein interactome map of D. melanogaster (interaction database BioGRID v 2.0, visualization software platform Osprey v. 1.2.0, ) which consisted of 7358 genes (vertices) and 24984 connections (edges) [47]. Out of 2574 PTZ regulated genes, 1633 were present in the fly interactome. We retrieved PTZ gene specific subinteractome that consisted of 1633 vertices and 1485 edges. In this subinteractome map, 632 genes were found to be loner, i.e., they did not show any within group interaction. We hereafter focused on within group interaction network which was comprised of 1001 genes and 1485 interactions (for interacting genes, see additional file 5). We next examined which of the 12 hrs gene(s) shows statistically significant overinteraction in the network of 1001 vertices and 1485 edges. Among 13 beginning phase, i.e., 12 hrs, genes present in the network, only the C-terminal Binding Protein (CtBP, CG7583) was found to overinteract (hypergeometric distribution after Bonferroni correction, p = 0.004; Table 3; Figure 5). CG7583 and its direct interacting partners, a network comprising of 17 genes, showed overrepresentation of various GO processes which were mainly related to transcriptional regulation and cell fate determination (Table 4). Transcriptional alteration was thus identified as the most proximal effect of PTZ. To complete adding direction, we retrieved enriched processes in genes which showed interaction with interacting partners of CG7583 in the self-interacting network of our PTZ genes, and so on, till completion; of 1001 genes, 898 were consumed by this CG7583 centered network. Enrichment of cell morphogenesis and protein import into nucleus; neuron differentiation, neurogenesis, axonogenesis, axon guidance, small GTPase mediated signal transduction, actin filament organization, cell growth, transmembrane receptor protein tyrosine kinase signaling pathway, eye photoreceptor cell differentiation, regulation of cell shape and regulation of cell size; phospholipase C activation and positive regulation of hydrolase activity was observed, in that order (for complete lists of enriched GO processes, see additional file 6). Broadly, process enrichment analysis guided by protein interactome suggested that chronic PTZ sequentially downregulates transcription, neurogenesis/axonogenesis/axon guidance and phospholipase C activation. This was consistent with original time series analysis presented above (Tables 1 and 2), except that glutamate metabolism related processes enriched on 7th day (Table 2) were not recovered by interactome guided analysis. Seventh day genes under these categories – CG7145, CG5320 (Gdh), CG14994 (Gad1), CG1743 (Gs2) and CG8430 (Got1) – are poorly connected in the entire fly interactome (range, 0–3 interactions). It is likely that non-recovery of glutamate metabolism related processes reflect poor interaction of the genes involved. Cumulatively, the above results suggested that sequential downregulation of gene expression, neurogenesis/axonogenesis/axon guidance, phospholipase C activation and glutamate metabolism characterize our fly behavioral model.

Bottom Line: Pathway overrepresentation analysis showed enrichment of Wnt signaling and other associated pathways in genes downregulated by PTZ.Mining of available transcriptomic and proteomic data pertaining to established rodent models of epilepsy and human epileptic patients showed overrepresentation of epilepsy associated genes in our PTZ regulated set.Amenable to modeling, our model offers a unique opportunity to further dissect epileptogenesis-like plasticity and to unravel mechanisms of long-term action of AEDs relevant in neuropsychiatric disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Genomics and Integrative Biology, Delhi University Campus, India.

ABSTRACT

Background: Rodent kindling induced by PTZ is a widely used model of epileptogenesis and AED testing. Overlapping pathophysiological mechanisms may underlie epileptogenesis and other neuropsychiatric conditions. Besides epilepsy, AEDs are widely used in treating various neuropsychiatric disorders. Mechanisms of AEDs' long term action in these disorders are poorly understood. We describe here a Drosophila systems model of PTZ induced locomotor plasticity that is responsive to AEDs.

Results: We empirically determined a regime in which seven days of PTZ treatment and seven days of subsequent PTZ discontinuation respectively cause a decrease and an increase in climbing speed of Drosophila adults. Concomitant treatment with NaVP and LEV, not ETH, GBP and VGB, suppressed the development of locomotor deficit at the end of chronic PTZ phase. Concomitant LEV also ameliorated locomotor alteration that develops after PTZ withdrawal. Time series of microarray expression profiles of heads of flies treated with PTZ for 12 hrs (beginning phase), two days (latent phase) and seven days (behaviorally expressive phase) showed only down-, not up-, regulation of genes; expression of 23, 2439 and 265 genes were downregulated, in that order. GO biological process enrichment analysis showed downregulation of transcription, neuron morphogenesis during differentiation, synaptic transmission, regulation of neurotransmitter levels, neurogenesis, axonogenesis, protein modification, axon guidance, actin filament organization etc. in the latent phase and of glutamate metabolism, cell communication etc. in the expressive phase. Proteomic interactome based analysis provided further directionality to these events. Pathway overrepresentation analysis showed enrichment of Wnt signaling and other associated pathways in genes downregulated by PTZ. Mining of available transcriptomic and proteomic data pertaining to established rodent models of epilepsy and human epileptic patients showed overrepresentation of epilepsy associated genes in our PTZ regulated set.

Conclusion: Systems biology ultimately aims at delineating and comprehending the functioning of complex biological systems in such details that predictive models of human diseases could be developed. Due to immense complexity of higher organisms, systems biology approaches are however currently focused on simpler organisms. Amenable to modeling, our model offers a unique opportunity to further dissect epileptogenesis-like plasticity and to unravel mechanisms of long-term action of AEDs relevant in neuropsychiatric disorders.

Show MeSH
Related in: MedlinePlus