Serotonin receptor 5-HT1A initiates serotonin autoregulation in drosophila neurons

Abstract

Serotonergic neurons produce extensively branched axons that fill most of then central nervous system, where they modulate behaviors such as mood, sleep, appetite, locomotion, and cognition. Proper behavioral output therefore depends on the precise outgrowth and targeting of serotonergic axons during development. Serotonergic neurons utilize serotonin as a signaling molecule prior to its role as a neurotransmitter. This process, termed serotonin autoregulation, regulates axon outgrowth, branching, and varicosity development of Drosophila serotonergic neurons. However, the underlying mechanism of serotonin autoregulation remains unknown. I therefore hypothesized that serotonin autoreceptors initiate autoregulation in serotonergic neurons. To test this, I adapted a primary neuron culture system in which Drosophila serotonergic neurons could be grown and unambiguously identified using Gal4-dependent expression of the fluorescent protein tdTomato. Next, I initiated autoregulation by applying exogenous serotonin to the cultured neurons. I found reduced axon outgrowth and branching, suggesting serotonergic neurons in culture respond similarly as previously reported in vivo. Lastly, I used a pharmacological agonist to activate the serotonin autoreceptor, 5-HT1A, to test its role in autoregulation. Neurons treated with agonist showed reduced axon outgrowth and branching, thereby mimicking the effects of serotonin application. Overall, my findings suggest a novel mechanism in which serotonin initiates autoregulation through activation of autoreceptors.