Big Lessons from Tiny Flies: Drosophila melanogaster as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems

Abstract

The brain of Drosophila melanogaster is comprised of some 100,000 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g., motor activity, reward and aversion, memory formation, feeding, sexual appetite, etc. Mammalian dopaminergic and serotonergic neurons are known to be heterogeneous. They differ in their projections and in their gene expression profile. A sophisticated genetic tool box is available, which allows for targeting virtually any gene with amazing precision in Drosophila melanogaster. Similarly, Drosophila genes can be replaced by their human orthologs including disease-associated alleles. Finally, genetic manipulation can be restricted to single fly neurons. This has allowed for addressing the role of individual neurons in circuits, which determine attraction and aversion, sleep and arousal, odor preference, etc. Flies harboring mutated human orthologs provide models which can be interrogated to understand the effect of the mutant protein on cell fate and neuronal connectivity. These models are also useful for proof-of-concept studies to examine the corrective action of therapeutic strategies. Finally, experiments in Drosophila can be readily scaled up to an extent, which allows for drug screening with reasonably high throughput.

Keywords: Drosophila; dopamine; neurodegeneration; neurotransmitter transporters; serotonin; vesicular monoamine transporters.

Figure 1

Drosophila melanogaster (A) and adult fly brain (B,C). (A): Image of adult female (left) and male (right) Canton-S Drosophila melanogaster; (B): Anterior view of adult fly brain carrying serotonin transporter protein trap (Bloomington Drosophila Stock Center no. 60529, Bloomington, IN, USA). The cell bodies of serotonergic neurons are labeled in green by expression of GFP; and (C): Posterior view of TH Gal4; mCD8:GFP adult fly brain: The dopaminergic neurons are delineated by their expressing the murine GFP-tagged CD8, which uniformly labels the neuronal membrane. ImageJ 3D Viewer plugin was used to generate the image. Anti-neuronal cadherin antibody (MNCD2, DSHB, University of Iowa, IA, USA, magenta (B) and blue (C)) was used to delineate the adult fly brain. Scale bar: 50 μm.

Figure 2

Distribution of dopaminergic (A) and serotonergic (B) neurons in adult fly brain. The dopaminergic and serotonergic neurons are distributed in various clusters in flies. Anti-TH antibody (Abcam, 128249, Cambridge, UK) was used to label dopaminergic neurons and serotonin transporter protein trap (bloomington stock no. 60529) was used to visualize serotonergic cell bodies in adult fly brain. PAM: Protocerebral anterior medial; PAL: Protocerebral anterior lateral; PPL: Posterior protocerebrum lateral; PPM: Protocerebral posterior medial; T1: Thoracic 1; SOG: Subesophagal ganglion; PLP: Posterior lateral protocerebrum; ADMP: Anterior dorsomedial protocerebrum; ALP: Anterior lateral protocerebrum; LP: Lateral protocerebrum; PMPM: Posterior medial posterior medial; SEL: Subesophageal lateral; CSD: Contralaterally projecting, serotonin-immunoreactive, deutocerebral; SEM: Medial subesophageal ganglion; PMPD: Posterior medial protocerebrum, dorsal; IP: Inferior medial protocerebral. Red dot: PPL1 dopaminergic neurones (A) that also produce serotonin. Black dot: Dopaminergic (A) and serotonergic (B) cell bodies.