http://precedings.nature.com/users/a0c3b4542bf278c1c60e27a360055bc7/ Documents posted by abhay sharma Nature Publishing Group en Nature Precedings http://precedings.nature.com/images/header_logo.gif http://precedings.nature.com http://precedings.nature.com/documents/3460/version/1 A male Drosophila model of locomotor deficit induced by chronic pentylenetetrazole (PTZ), a proconvulsant used to model epileptogenesis in rodents, has recently been described. Antiepileptic drugs (AEDs) ameliorate development of this behavioral abnormality. Time-series of microarray profiling of heads of male flies treated with PTZ has shown epileptogenesis-like transcriptomic perturbation in the fly model. Gender differences are known to exist in neurological and psychiatric conditions including epileptogenesis. We describe here the effects of chronic PTZ in Drosophila females, and compare the results with the male model. As in males, chronic PTZ was found found to cause a decreased climbing speed in females. In males, overrepresentation of Wnt, MAPK, TGF-beta, JAK-STAT, Cell communication, and Dorso-Ventral axis formation pathways in downregulated genes was previously described. Of these, female genes showed enrichment only for Dorso-Ventral axis formation. Most significant, ribosomal pathway was uniquely overrepresented in genes downregulated in females. Gender differences thus exist in the Drosophila model. Gender neutral, Dorso-Ventral axis formation may be considered as the candidate causal pathway in chronic pentylenetetrazole induced behavioral deficit. Prior evidence of developmental mechanisms in epileptogenesis underscores the usefulness of fly model. Gender specific pathways may provide a lead for understanding brain dimorphism in neuropsychiatric disorders. http://precedings.nature.com/documents/3460/version/1 Mon, 27 Jul 2009 20:02:00 UTC Gender differences in a Drosophila transcriptomic model of chronic pentylenetetrazole induced behavioral deficit hdl:10101/npre.2009.3460.1 2009-07-27 Abhay Sharma Nature Precedings 2009-07-27T20:02:00Z Manuscript Genetics & Genomics Neuroscience Pharmacology Bioinformatics http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/3447/version/1 Rodent kindling induced by pentylenetetrazole (PTZ) is an established model of epileptogenesis and antiepileptic drug (AED) testing. Recently, a Drosophila systems model has been described in which chronic PTZ causes a decreased climbing speed in adult males on 7th day. Some AEDs ameliorate development of this locomotor deficit. Time-series of microarray expression profiles of heads of flies treated with PTZ has been found to resemble transcriptomic alterations associated with epileptogenesis. In the fly model, withdrawal from seven day long PTZ treatment causes an increased climbing speed on 7th consequent day. Here, we present a systems model of the post-PTZ withdrawal regime. Unlike AED-untreated individuals, flies treated with any of the five AEDs after PTZ discontinuation exhibited normal climbing speed on 7th day, i.e., 14th day from the beginning of PTZ treatment. Time-series of microarray expression profiles of fly heads comparing control PTZ- and AED-untreated, and AED-untreated post PTZ withdrawal groups showed differentially expressed genes throughout. These genes enriched gene ontology (GO) molecular functions including transcription regulator and GTPase regulator activities. Interestingly, expression profiles of fly heads comparing control PTZ- and AED-untreated, and AED-treated post PTZ withdrawal groups showed neutralization of transcription regulator and GTPase regulator activities by the AEDs. Further transcriptomic analysis based on overinteraction in protein interactome and enrichment of miRNA targets implicated axon guidance and neuronal remodeling related perturbations in the fly model. Differential expression of genes belonging to transcription regulator and GTPase regulator activities have previously been reported in post-epileptogenesis in established rodent models. Also, axon guidance and neuronal remodeling related alterations have been implicated in epilepsy. The Drosophila model thus provides a unique opportunity to dissect long-term plasticity relevant in epileptogenesis at cellular and molecular levels. Besides, the model also offers an excellent system to efficiently screen agents with potential therapeutic activity. http://precedings.nature.com/documents/3447/version/1 Tue, 21 Jul 2009 16:40:03 UTC A Drosophila systems model of withdrawal from chronic pentylenetetrazole relevant in post-epileptogenesis hdl:10101/npre.2009.3447.1 2009-07-21 Abhay Sharma Nature Precedings 2009-07-21T16:40:03Z Manuscript Genetics & Genomics Neuroscience Pharmacology Bioinformatics http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/3429/version/1 In a newly described Drosophila model, two of the five antiepileptic drugs (AEDs) tested, sodium valproate (NaVP) and levetiracetam (LEV), not ethosuximide (ETH), gabapentin (GBP) and vigabatrin (VGB), ameliorate development of chronic pentylenetetrazole (PTZ) induced locomotor alteration. To further characterize the model, we analyze here the microarray expression profile of heads of flies treated with depolarizing compound potassium chloride (KCl). Surprisingly, microarray clustering showed unexpected similarity among KCl, LEV and NaVP. Further, like the two effective AEDs in the fly model, KCl regulated genes overrepresented ribosomal pathway. Interestingly, KCl also ameliorated development of locomotor deficit in the chronic PTZ model. Both transcriptomic and behavioral analyses thus showed LEV- and NaVP- like neuroprotective effect of KCl. This is consistent with neuroprotective effect of KCl observed previously in mammalian system. The Drosophila model thus provides a unique opportunity to understand long term mechanisms of neuroactive compounds. http://precedings.nature.com/documents/3429/version/1 Fri, 17 Jul 2009 14:41:20 UTC A novel Drosophila transcriptomic and behavioral model detects potassium chloride with therapeutic potential hdl:10101/npre.2009.3429.1 2009-07-17 Abhay Sharma Nature Precedings 2009-07-17T14:41:20Z Manuscript Genetics & Genomics Neuroscience Pharmacology Bioinformatics http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/3418/version/1 A Drosophila behavioral and transcriptomic model of locomotor plasticity induced by chronic pentylenetetrazole (PTZ) has recently been developed. In this model, two of the five antiepileptic drugs (AEDs) tested, sodium valproate (NaVP) and levetiracetam (LEV), not ethosuximide (ETH), gabapentin (GBP) and vigabatrin (VGB), ameliorate development of chronic PTZ induced locomotor alteration. Transcriptomic effect of the AEDs and PTZ in fly head has been described. Here, we analyze microarray expression profile of heads of flies treated with the convulsants tetraethylammonium chloride (TEA) and pilocarpine hydrochloride (PILO). Strikingly, microarray clustering placed TEA, not PILO, with LEV and NaVP in one group that was distinct from the other one consisting of PTZ, GBP, VGB and ETH. Further, like LEV and NaVP, TEA regulated genes overrepresented ribosomal and energy metabolic pathways. Also, TEA, like LEV and NaVP, ameliorated development of locomotor deficit in the chronic PTZ model. Both transcriptomic and behavioral analyses thus demonstrated LEV- and NaVP- like neuroprotective effect of TEA. Our results are consistent with earlier paradoxical evidence suggesting that TEA may be neuroprotective. Amenability of Drosophila model thus provides an excellent opportunity to understand long term mechanisms of action of centrally acting drugs in molecular details. http://precedings.nature.com/documents/3418/version/1 Fri, 10 Jul 2009 14:58:20 UTC A novel Drosophila post-genomic CNS drug discovery model detects tetraethylammonium chloride with therapeutic potential hdl:10101/npre.2009.3418.1 2009-07-10 Abhay Sharma Nature Precedings 2009-07-10T14:58:20Z Manuscript Genetics & Genomics Neuroscience Pharmacology Bioinformatics http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/3396/version/1 Mechanisms of long term action of antiepileptic drugs (AEDs), used in treating epilepsy and many other neurological and psychiatric disorders, are poorly understood. Recently, a novel Drosophila transcriptomic model of locomotor plasticity induced by chronic pentylenetetrazole (PTZ), a chemoconvulsant commonly used to model epileptogenesis and test AEDs in rodents, has been described. In this model, two of the five AEDs tested, sodium valproate (NaVP) and levetiracetam (LEV), not ethosuximide (ETH), gabapentin (GBP) and vigabatrin (VGB), ameliorate development of chronic PTZ induced locomotor alteration. Here, we describe transcriptomic effect of the AEDs in the fly model. Singular treatment with ETH, GBP and VGB in general caused downregulation of genes. In contrast, similar treatment with NaVP and LEV caused upregulation. The GBP and NaVP gene sets showed enrichment of the ribosomal and energy metabolic pathways. The network partners of ETH, VGB and LEV regulated genes in the available interactome map were also found to overrepresent the ribosomal pathway. Unlike PTZ alone, PTZ and LEV combination treatment was found to cause differential regulation of genes that too enriched the ribosomal and energy metabolic pathways. Cumulatively, we provide transcriptomic evidence that suggests involvement of ribosomal and energy metabolic mechanisms in AED action. The Drosophila model provides an excellent opportunity to further understand mechanisms of AED action in molecular details. http://precedings.nature.com/documents/3396/version/1 Tue, 07 Jul 2009 16:27:35 UTC Transcriptomic analysis implicates ribosomal and energy metabolic pathways in antiepileptic drug action in a Drosophila model hdl:10101/npre.2009.3396.1 2009-07-07 Abhay Sharma Nature Precedings 2009-07-07T16:27:35Z Manuscript Genetics & Genomics Neuroscience Pharmacology Bioinformatics http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/3312/version/1 Transgenerational spermatogenic inheritance of adult male acquired CNS gene expression characteristics has recently been discovered using a Drosophila systems model. In this novel mode of inheritance, transcriptomic alteration induced by the neuroactive drug pentylenetetrazole (PTZ) has been found to leak to future generations. Here, the available microarray gene expression data pertaining to CNS and/or testis of exposed F0 and the resulting F1 and F2 generations has been pooled and analyzed in an unbiased manner at four levels, namely, biological processes and pathways, protein interactome networks, miRNA-targets, and microarray expression profile similarities. Enrichment for processes related to translation, energy metabolism, cell proliferation, cell differentiation, secretion, central nervous system development, germ cell development, gamete generation, wing development, nutrition etc. was observed. Also, ribosome, oxidative phosphorylation and, to a lesser extent, wingless signaling pathway showed overrepresentation. In the proteomic interactome map, the cell cycle gene Ras85D exhibited overinteraction. In miRNA-target network, the fly transgenerational genes showed overrepresentation of mir-315 targets. Transcriptomic matching revealed overlap of transgenerational set with genes related to epigenetic drug treatment, stem cells, Myc targets and miRNA targets. Many of the findings were consistent with the existing epigenetic evidence in complex mammalian traits. Converging evidence suggests that ribosomal RNA and proteins may serve as candidate biomarkers of transgenerational environmental effect. A compelling systems biology frame-work integrative of transgenerational epigenetic inheritance is suggested. Nutrient, circulating peptide hormone, Myc, Wnt, and stem cell signaling pathways constitute the frame-work. The analysis has implications in explaining missing heritability in complex traits including common human disorders. The fly model offers an excellent opportunity to understand somatic and germline communication, and epigenetic memory formation and its retention across generations in molecular details. http://precedings.nature.com/documents/3312/version/1 Fri, 05 Jun 2009 20:16:28 UTC Systems level analysis of transgenerational spermatogenic inheritance predicts biomarkers and underlying pathways hdl:10101/npre.2009.3312.1 2009-06-05 Abhay Sharma Nature Precedings 2009-06-05T20:16:28Z Manuscript Genetics & Genomics http://creativecommons.org/licenses/by/3.0/