Genotype-Specific Electroretinogram Signatures in Drosophila : Implications for Neurodegeneration Models Using w ¹¹¹⁸ Backgrounds

Drosophila melanogaster serves as a powerful model for studying neurodegenerative diseases, often employing the GAL4-UAS system for targeted gene expression. Electroretinograms (ERGs) provide a robust in vivo functional readout of neuronal integrity and are increasingly used to assess disease progression and therapeutic interventions in these models. However, the genetic background upon which these models are built, particularly the widely used w ¹¹¹⁸ white-eyed mutant, can significantly influence baseline ERG characteristics. This study systematically characterizes ERG responses in wild-type Canton S (CS), w ¹¹¹⁸ , and a w ¹¹¹⁸ line carrying a UAS-hPLD1 construct (which includes a mini-white gene). We demonstrate profound differences in ERG amplitudes, waveforms, and responses to varying light stimuli (intensity and duration) between these genotypes, as well as significant sex-specific variations. Notably, w ¹¹¹⁸ flies exhibit markedly larger ERG amplitudes compared to CS, while the hPLD1 line shows partial compensation. We also introduce a novel quadrant-based analysis of the receptor potential, revealing distinct “fingerprints” for each genotype. These findings underscore that the w ¹¹¹⁸ background is not electrophysiologically neutral and can intrinsically alter neuronal responses. This has critical implications for interpreting ERG data from neurodegeneration models, as these background effects could mask or mimic disease-related changes. Researchers must consider these baseline differences and potential sex-specific effects to accurately attribute observed ERG phenotypes to the gene or condition under investigation.