ABSTRACT
We isolated two mutants defective in the uptake of exogenous serotonin (5-HT) into the neurosecretory motor neurons of Caenorhabditis elegans. These mutants were hypersensitive to exogenous 5-HT and hyper-responsive in the experience-dependent enhanced slowing response to food modulated by 5-HT. The two allelic mutations defined the gene mod-5 (modulation of locomotion defective), which encodes the only serotonin reuptake transporter (SERT) in C. elegans. The selective serotonin reuptake inhibitor fluoxetine (Prozac) potentiated the enhanced slowing response, and this potentiation required mod-5 function, establishing a 5-HT- and SERT-dependent behavioral effect of fluoxetine in C. elegans. By contrast, other responses of C. elegans to fluoxetine were independent of MOD-5 SERT and 5-HT. Further analysis of the MOD-5-independent behavioral effects of fluoxetine could lead to the identification of novel targets of fluoxetine and could facilitate the development of more specific human pharmaceuticals.
Subject(s)
Carrier Proteins/genetics , Carrier Proteins/metabolism , Fluoxetine/pharmacology , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Membrane Transport Proteins , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/metabolism , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Caenorhabditis elegans , Caenorhabditis elegans Proteins , Cells, Cultured , Cloning, Molecular , DNA Mutational Analysis , Drug Synergism , Feeding Behavior/drug effects , Feeding Behavior/physiology , Genetic Complementation Test , Helminth Proteins/genetics , Helminth Proteins/metabolism , Lasers , Microscopy, Fluorescence , Molecular Sequence Data , Motor Activity/drug effects , Motor Activity/physiology , Motor Neurons/cytology , Motor Neurons/metabolism , Motor Neurons/radiation effects , Mutagenesis , Mutation , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Sequence Homology, Amino Acid , Serotonin/pharmacokinetics , Serotonin Plasma Membrane Transport ProteinsABSTRACT
Caenorhabditis elegans modulates its locomotory rate in response to its food, bacteria, in two ways. First, well-fed wild-type animals move more slowly in the presence of bacteria than in the absence of bacteria. This basal slowing response is mediated by a dopamine-containing neural circuit that senses a mechanical attribute of bacteria and may be an adaptive mechanism that increases the amount of time animals spend in the presence of food. Second, food-deprived wild-type animals, when transferred to bacteria, display a dramatically enhanced slowing response that ensures that the animals do not leave their newly encountered source of food. This experience-dependent response is mediated by serotonergic neurotransmission and is potentiated by fluoxetine (Prozac). The basal and enhanced slowing responses are distinct and separable neuromodulatory components of a genetically tractable paradigm of behavioral plasticity.
Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans/physiology , Dopamine/physiology , Environment , Mixed Function Oxygenases , Motor Activity/physiology , Serotonin/physiology , Animals , Catalase/genetics , Dopamine/pharmacology , Escherichia coli/physiology , Fluoxetine/pharmacology , Food Deprivation/physiology , Fungal Proteins/genetics , Helminth Proteins/genetics , Mechanoreceptors/physiology , Motor Activity/drug effects , Mutation/physiology , Neurons/physiology , Selective Serotonin Reuptake Inhibitors/pharmacology , Time Factors , Trans-Activators/geneticsABSTRACT
The Caenorhabditis elegans gene eat-4 affects multiple glutamatergic neurotransmission pathways. We find that eat-4 encodes a protein similar in sequence to a mammalian brain-specific sodium-dependent inorganic phosphate cotransporter I (BNPI). Like BNPI in the rat CNS, eat-4 is expressed predominantly in a specific subset of neurons, including several proposed to be glutamatergic. Loss-of-function mutations in eat-4 cause defective glutamatergic chemical transmission but appear to have little effect on other functions of neurons. Our data suggest that phosphate ions imported into glutamatergic neurons through transporters such as EAT-4 and BNPI are required specifically for glutamatergic neurotransmission.
