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A Drosophila systems model of withdrawal from chronic pentylenetetrazole relevant in post-epileptogenesis

Priyanka Singh¹, Farhan Mohammad² & Abhay Sharma¹

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1. Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Mall Road, Delhi University Campus, Delhi 110007, India
2. Institute of Genomics and Integrative Biology, Council of Scientific and Industrial Research, Mall Road, Delhi University Campus, Delhi 110007, India, Present address: Tata Institute of Fundamental Research, Department of Biological Research, Dr. Homi Bha

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Document Type:

Manuscript

Date:

Received 21 July 2009 16:19 UTC; Posted 21 July 2009

Subjects:

Genetics & Genomics, Neuroscience, Pharmacology, Bioinformatics

Tags:

• Drosophila
• systems model
• epileptogenesis
• pentylenetetrazole
• antiepileptic drugs
• ethosuximide
• gabapentin
• vigabatrin
• levetiracetam
• sodium valproate
• microarray
• locomotor behavior
• gene expression
• pathways

Abstract:

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.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Singh, Priyanka, Mohammad, Farhan, and Sharma, Abhay. A Drosophila systems model of withdrawal from chronic pentylenetetrazole relevant in post-epileptogenesis . Available from Nature Precedings <http://hdl.handle.net/10101/npre.2009.3447.1> (2009)

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