Gender differences in a Drosophila transcriptomic model of chronic pentylenetetrazole induced behavioral deficit

Abstract

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 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. Surprisingly, the ribosomal pathway was uniquely overrepresented in genes downregulated in females. Gender differences thus exist in the Drosophila model. Gender neutral, the developmental pathway 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 may support potential usefulness of the fly model. Given this, gender specific pathways identified here may provide a lead for further understanding brain dimorphism in neuropsychiatric disorders.

Figure 1. Time-series of microarray gene expression profiles.

Profiles were generated from heads of PTZ treated flies. Hierarchical clustering of female profiles alone (a), and both male and female profiles together (b). Male microarrays were described previously . City Block similarity metric and average linkage methods were used for clustering of arrays. Each profile represents mean of normalized log₂ ratio (635/532) of four biological replicates with balanced dye-swaps. The cluster was generated using Acuity 4.0.

Figure 2. Downregulation of genes related to Dorso-ventral axis formation pathway.

Green boxes indicate genes downregulated in females after chronic PTZ. Differentially expressed genes in all the three time-points combined were used for pathway mapping. Dorso-ventral axis formation pathway was previously found to be enriched in males also .

Figure 3. Downregulation of genes related to the ribosomal pathway.

Green boxes indicate genes downregulated in females after chronic PTZ. Differentially expressed genes in all the three time-points combined were used for pathway mapping. The ribosomal pathway was previously not found to be enriched in males . Grey and white boxes indicate presence and absence of Drosophila melanogaster genes in the pathway, respectively.