Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine neurotransmitter that has been implicated in regulation of mood, behavior and satiety. Drugs that modulate serotonin signaling, such as selective serotonin reuptake inhibitor fluoxetine (Prozac), are potent antidepressants. To understand the role of fluoxetine on serotonergic signaling in the context of a whole animal, we study the effect of fluoxetine and SERT (serotonin reuptake transporter)-deficient mutant
mod-5 on serotonergic neurons. Specifically, we ask whether all serotonergic neurons can synthesize serotonin de novo, if every serotonin-producing neuron can re-uptake serotonin, and how blockage of MOD-5 affects serotonin signaling. Serotonergic system in C.elegans includes nine neurons in five classes: NSM, ADF, HSN, AIM pairs of neurons and single RIH neuron (1, 2). We have previously reported that RIH and AIM neurons have very low expression levels of
tph-1, the key enzyme for serotonin biosynthesis, but significant levels of serotonin, suggesting that these neurons receive serotonin mainly by reuptaking. We confirm this hypothesis by serotonin immunostaining of fluoxetine-treated wild type animals and
mod-5 mutants - in these animals RIH and AIM neurons has no detectable serotonin. We found that the SERT gene
mod-5 is expressed in NSM, ADF, RIH and AIM neurons, but not in HSN. Consistent with this observation, NSM, ADF, RIH and AIM neurons can uptake exogenous serotonin, but HSN cannot. By expressing
tph-1 in specific neurons in
tph-1 mutant background, we have found that RIH and AIM neurons can uptake serotonin that produced in NSM and in ADF. NSM can uptake serotonin from ADF, but ADF cannot efficiently uptake serotonin from NSM. Probably, ADF has no access to serotonin that produced in NSM. Thus, there are three types of serotonergic neurons in C.elegans - serotonin producing and absorbing (NSM, ADF), serotonin producing (HSN), serotonin-absorbing (RIH, AIM). RIH and AIM also express
cat-1, which loads serotonin into synaptic vesicles for regulated serotonin release. Clearly, for the pathways mediated by RIH and AIM, blockage of MOD-5 will have the effect of inhibiting, not enhancing, serotonin signals. We are currently investigating how serotonin-deficient
tph-1 and SERT-deficient
mod-5 mutants as well as serotonin and fluoxetine treatment affect downstream targets of serotonin signaling to figure out SERT-dependent and -independent functions of fluoxetine, the influence of serotonin excess or deficit on the organism physiology, and the role of serotonin-absorbing neurons in serotonin signaling. (1) HR Horvitz et al. Science. 1982 May 28;216(4549):1012-4. (2) Sze et al. Nature. 2000 Feb 3;403(6769):560-4.