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

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Abstract 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. Graphical Abstract Highlights ERG profiles differ significantly between CS, w 1118 , and w 1118 ; UAS-hPLD1 flies. The w 1118 background, common in GAL4-UAS studies, exhibits distinct ERG features. Sex-specific differences in ERG responses are prominent and genotype-dependent. UAS-hPLD1 insertion (with mini-white) partially alters the w 1118 ERG phenotype. Results caution the interpretation of ERG data in w 1118 neurodegeneration models.

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