Dysregulation of dopamine (DA) dynamics (synthesis, secretion, and metabolism) and signaling underlies a number of symptoms seen in various neurological and psychiatric diseases. Core components of DA dynamics and signaling are being extensively characterized in diverse model systems. In contrast, very little is known about the genes and cellular pathways that fine-tune the activity of this neuromodulator in vivo.
To identify novel factors that regulate DA dynamics, we have been performing a forward genetic screen in Drosophila melanogaster. We first screened for novel genes that affect cuticle pigmentation (a DA dependent phenotype) in adult flies using chemical mutagenesis/clonal analysis and tissue specific RNAi. Through this primary screen, we identified 123 genes, ~85% of which are evolutionarily conserved between flies and human. We then performed a Drosophila Activity Monitor (DAM) based secondary screen to determine whether these genes exhibit a defect in basal activity upon dopaminergic neuronal knockdown. Genes that exhibit strong hypo- or hyperactivity are being prioritized for a tertiary analysis to determine whether dopaminergic neuron specific knockdown of these genes directly affect brain DA levels.
We are currently focusing on genes whose human homologs have been linked to Autism Spectrum Disorders (ASD). Interestingly, 20 of the 123 genes we isolated in our primary screen have human homologs that have been strongly linked to ASD including gigas (TSC2), Prosap (SHANK1-3), slp1 (FOXG1), and Usp7 (USP7). By studying the molecular function of these genes in the context of dopamine dynamics and signaling, we hope to understand how defects in these genes may contribute to some of the symptoms found in ASD patients.