Abstract
We have taken advantage of a newly described Drosophila model to gain insights into the potential mechanism of antiepileptic drugs (AEDs), a group of drugs that are widely used in the treatment of several neurological and psychiatric conditions besides epilepsy. In the recently described Drosophila model that is inspired by pentylenetetrazole (PTZ) induced kindling epileptogenesis in rodents, chronic PTZ treatment for 7 days causes a decreased climbing speed and an altered CNS transcriptome, with the latter mimicking gene expression alterations reported in epileptogenesis. In the model, an increased climbing speed is further observed 7 days after withdrawal from chronic PTZ. We used this post-PTZ withdrawal regime to identify potential AED mechanism. In this regime, treatment with each of the five AEDs tested, namely, ethosuximide, gabapentin, vigabatrin, sodium valproate, and levetiracetam, resulted in rescuing of the altered climbing behavior. The AEDs also normalized PTZ withdrawal induced transcriptomic perturbation in fly heads; whereas AED untreated flies showed a large number of up- and down-regulated genes which were enriched in several processes including gene expression and cell communication, the AED treated flies showed differential expression of only a small number of genes that did not enrich gene expression and cell communication processes. Gene expression and cell communication related upregulated genes in AED untreated flies overrepresented several pathways – spliceosome, RNA degradation, and ribosome in the former category, and inositol phosphate metabolism, phosphatidylinositol signaling, endocytosis, and hedgehog signaling in the latter. Transcriptome remodeling effect of AEDs was overall confirmed by microarray clustering that clearly separated the profiles of AED treated and untreated flies. Besides being consistent with previously implicated pathways, our results provide evidence for a role of other pathways in psychiatric drug mechanism. Overall, we provide an amenable model to understand neuropsychiatric mechanism in cellular and molecular terms.
Highlights
Drugs used in the treatment of psychiatric disorders are mostly known to target neurotransmitter receptors
Behavioral effect of PTZ is normalized by antiepileptic drugs (AEDs) We first examined the behavioral pharmacology of AEDs in the fly model
Pathway enrichment analysis To gain further insights into the normalizing effect of AEDs on PTZ withdrawal induced transcriptomic perturbation, we examined if gene expression (GO:0010467) and cell communication (GO:0007154) related upregulated genes in AED untreated flies on 10th day enrich specific pathways
Summary
Drugs used in the treatment of psychiatric disorders are mostly known to target neurotransmitter receptors. In addition to receptor mediated acute biochemical effects that may explain short-term clinical response, these drugs are considered to exert other long term therapeutic effects that may not be directly related to receptor mechanisms (Molteni et al, 2009). These long term neuroprotective mechanisms underlying psychiatric drug action are poorly understood (McLoughlin et al, 2009). A meta-analysis has recently revealed that gene expression profiles of brains from persons with major depressive disorder show decreased expression of genes related to glutamate transport and metabolism, neurotrophic signaling and MAP kinase pathways, and that genes in these pathways show increased expression in the brains of rodents exposed to antidepressant treatments (Altar et al, 2009)
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