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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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Enrichment of Dorso-ventral axis formation pathway. Pink boxes indicate CG7583 extended network genes that overrepresent one or more GO processes. For details, see text.
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Figure 11: Enrichment of Dorso-ventral axis formation pathway. Pink boxes indicate CG7583 extended network genes that overrepresent one or more GO processes. For details, see text.

Mentions: We next examined enrichment of biochemical and signaling pathways in all 338 genes which were part of enriched biological processes in CG7583 centered network, listed in additional file 6. Although no pathway was found to be enriched after Bonferroni correction for multiple hypotheses testing, our gene set overrepresented various pathways based on unadjusted p values (Table 5). Since enrichment of these pathways is consistent with process enrichment analysis presented above – TGF-beta signaling pathway and Wnt signaling pathway are consistent with neurogenesis/axonogenesis/axon guidance, for example – we considered the enriched pathways as significant. Genes showing downregulation in PTZ fly model are indicated in the enriched pathways shown in Figures 6, 7, 8, 9, 10, 11. Remarkably, Wnt signaling which is the most significant pathway in our analysis has previously been implicated in epilepsy [48]. As depicted in Figures 6, Wnt signaling is directly connected to TGF-beta (Figure 7) and MAPK signaling (Figure 8) pathways. Further, one or more of these pathways are also linked to JAK-STAT (Figure 9) and Cell Communication (Figure 10) pathways. Therefore, except Dorso-Ventral Axis Formation (Figure 11) which does not show any direct or indirect connection with Wnt signaling, all other five pathways enriched in our gene set are marked by biological plausibility in epileptogenesis.


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

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

Enrichment of Dorso-ventral axis formation pathway. Pink boxes indicate CG7583 extended network genes that overrepresent one or more GO processes. For details, see text.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 11: Enrichment of Dorso-ventral axis formation pathway. Pink boxes indicate CG7583 extended network genes that overrepresent one or more GO processes. For details, see text.
Mentions: We next examined enrichment of biochemical and signaling pathways in all 338 genes which were part of enriched biological processes in CG7583 centered network, listed in additional file 6. Although no pathway was found to be enriched after Bonferroni correction for multiple hypotheses testing, our gene set overrepresented various pathways based on unadjusted p values (Table 5). Since enrichment of these pathways is consistent with process enrichment analysis presented above – TGF-beta signaling pathway and Wnt signaling pathway are consistent with neurogenesis/axonogenesis/axon guidance, for example – we considered the enriched pathways as significant. Genes showing downregulation in PTZ fly model are indicated in the enriched pathways shown in Figures 6, 7, 8, 9, 10, 11. Remarkably, Wnt signaling which is the most significant pathway in our analysis has previously been implicated in epilepsy [48]. As depicted in Figures 6, Wnt signaling is directly connected to TGF-beta (Figure 7) and MAPK signaling (Figure 8) pathways. Further, one or more of these pathways are also linked to JAK-STAT (Figure 9) and Cell Communication (Figure 10) pathways. Therefore, except Dorso-Ventral Axis Formation (Figure 11) which does not show any direct or indirect connection with Wnt signaling, all other five pathways enriched in our gene set are marked by biological plausibility in epileptogenesis.

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