Distinct contribution of axonal and somatodendritic serotonin transporters in drosophila olfaction

• Published in: Neuropharmacology Vol. 161; p. 107564
• Main Authors: Kasture, Ameya Sanjay, Bartel, Daniela, Steinkellner, Thomas, Sucic, Sonja, Hummel, Thomas, Freissmuth, Michael
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.12.2019
• Subjects: Animals; Animals, Genetically Modified; Axons - metabolism; Axons - physiology; Cell Line; Central Nervous System Depressants - pharmacology; Dendrites - metabolism; Dendrites - physiology; Drosophila; Drosophila melanogaster - physiology; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Drosophila Proteins - physiology; ER-Export; Ethanol - pharmacology; Humans; Interneurons - drug effects; Odor perception; Point Mutation - genetics; Primary Cell Culture; Protein Folding; Raphe Nuclei - cytology; Raphe Nuclei - metabolism; Rats; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin Plasma Membrane Transport Proteins - physiology; Serotonin transporter; Smell - genetics; Smell - physiology; Somatodendritic localization; Odor perception; Somatodendritic localization; Serotonin transporter; ER-Export; Drosophila
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2019.03.007

The serotonin transporter (SERT) regulates serotonergic neurotransmission by retrieving released serotonin and replenishing vesicular stores. SERT is not only delivered to axons but it is also present on the neuronal soma and on dendrites. It has not been possible to restrict the distribution of SERT without affecting transporter function. Hence, the physiological role of somatodendritic SERT remains enigmatic. The SERT C-terminus harbors a conserved RI-motif, which recruits SEC24C, a cargo receptor in the coatomer protein-II coat. Failure to engage SEC24C precludes axonal enrichment of SERT. Here we introduced a point mutation into the RI-motif of human SERT causing confinement of the resulting - otherwise fully functional - hSERT-R607A on the somatodendritic membrane of primary rat dorsal raphe neurons. Transgenic expression of the corresponding Drosophila mutant dSERT-R599A led to its enrichment in the somatodendritic compartment of serotonergic neurons in the fly brain. We explored the possible physiological role of somatodendritic SERT by comparing flies harboring wild type SERT and dSERT-R599A in a behavioral paradigm for serotonin-modulated odor perception. When globally re-expressed in serotonergic neurons, wild type SERT but not dSERT-R599A restored ethanol preference. In contrast, dSERT-R599A restored ethanol preference after targeted expression in contralaterally projecting, serotonin-immunoreactive deuterocerebral (CSD) interneurons, while expression of wild type SERT caused ethanol aversion. We conclude that, in CSD neurons, (i) somatodendritic SERT supports ethanol attraction, (ii) axonal SERT specifies ethanol aversion, (iii) the effect of axonal SERT can override that of somatodendritic SERT. These observations demonstrate a distinct biological role of somatodendritic and axonal serotonin transport. This article is part of the issue entitled ‘Special Issue on Neurotransmitter Transporters’. [Display omitted] •HSERT-R607A mutant can be used to study the contribution of somatodendritic SERT.•In fruit flies somatodendritic and axonal SERT supported distinct odor responses.•The insights have implications for the antidepressant action of SERT inhibitors.