Serotonin signaling in C. elegans

Abstract

Wild-type animals that have been acutely food deprived slow their locomotory rate upon encountering bacteria more than do well-fed animals. This behavior, called the enhanced slowing response, is partly serotonin (5-HT) dependent. Animals mutant for the 5-HT reuptake transporter gene mod-5 slow even more than wild-type animals because endogenous 5-HT activity is potentiated. This behavior, called the hyperenhanced slowing response, can be suppressed by mutations in genes that encode proteins important for 5-HT signaling, like the 5-HT receptor encoded by mod-1 and the Ga subunit of a G protein encoded by goa-1. This ability to suppress indicates that these genes likely act downstream of or in parallel to one or more 5-HT synapse(s) that mediate(s) the enhanced slowing response. To find genes that play a role in 5-HT signaling, we screened for suppressors of the 5-HT hypersensitivity of mod-5. We found at least seven alleles of goa-i and at least two alleles of mod-1. This shows that our screen is able to target genes that play a role in endogenous 5-HT signaling. We identified two alleles of the FMRFamide-encoding gene fp-1, which was known to mediate paralysis in exogenous 5-HT. We showed that loss-of-function mutations in flp-1 confer an enhanced slowing response defect. We also identified an allele of abts-1, which encodes a bicarbonate transporter, and showed that it has defects in cholinergic signaling. We identified three mutants that show linkage to LG I, four to II, three to V and one to X, most of which display defects consistent with a role in 5-HT signaling.

(cont.) We used a candidate gene approach to find that deletions in ser-4, which encodes a metabotropic 5-HT receptor, confer 5-HT resistance. ser-4 acts redundantly with the ionotropic 5-HT receptor mod-1 to suppress the hyperenhanced slowing response of mod-5. Our genetic analysis suggests that ser-4 acts in a pathway with goa-1, in parallel to mod-1. We found that the enhanced slowing response defect of flp-1 is primarily due to its defect in transmitting a 5-HT signal and that flp-1 likely acts downstream of ser-4 and mod-1.