A Genetic Survey of Fluoxetine Action on Synaptic Transmission in <i>Caenorhabditis elegans</i>

Kullyev, Andrey; Dempsey, Catherine; Miller, Sarah; Kuan, Chih Jen; Hapiak, Vera; Komuniecki, Richard; Griffin, Christine T.; Sze, Ji Ying

doi:10.1534/genetics.110.118877

Cited by 48 publications

(69 citation statements)

References 78 publications

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“…1B, Table S1). These results confirm the opposing effects of Mianserin and Fluoxetine on synaptic release of neurotransmitters, with Mianserin increasing and Fluoxetine decreasing the release (Nurrish et al ., 1999; Kullyev et al ., 2010). …”

Section: Resultsmentioning

confidence: 99%

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

et al. 2015

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SummaryOxidative stress has long been associated with aging and has recently been linked to psychiatric disorders, including psychosis and depression. We identified multiple antipsychotics and antidepressants that extend Caenorhabditis elegans lifespan and protect the animal from oxidative stress. Here, we report that atypical antidepressants activate a neuronal mechanism that regulates the response to oxidative stress throughout the animal. While the activation of the oxidative stress response by atypical antidepressants depends on synaptic transmission, the activation by reactive oxygen species does not. Lifespan extension by atypical antidepressants depends on the neuronal oxidative stress response activation mechanism. Neuronal regulation of the oxidative stress response is likely to have evolved as a survival mechanism to protect the organism from oxidative stress, upon detection of adverse or dangerous conditions by the nervous system.

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Section: Resultsmentioning

confidence: 99%

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

et al. 2015

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“…This suggests that loss of MOD-5/SERT function increases 5-HT inputs to the neuronal circuit, resulting in behavioral sensitization. Our laboratory has identified that, out of 5 classes of a total of 9 neurons that accumulate 5-HT in C. elegans , a pair of AIM and a single RIH interneurons are 5-HT-absorbing neurons (Kullyev et al, 2010). Here, we report that the MOD-5/SERT function in AIM and RIH neurons controls the response to the experience of food deprivation.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Extrasynaptic 5-HT by Serotonin Reuptake Transporter Function in 5-HT-Absorbing Neurons Underscores Adaptation Behavior in Caenorhabditis elegans

Jafari

Xie

Kullyev

et al. 2011

Journal of Neuroscience

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Serotonin (5-HT)-absorbing neurons use serotonin reuptake transporter (SERT) to uptake serotonin (5-HT) from extracellular space but do not synthesize it. While 5-HT-absorbing neurons have been identified in diverse organisms from C. elegans to humans, their function has not been elucidated. Here, we show that SERT in 5-HT-absorbing neurons controls behavioral response to food deprivation in C. elegans. The AIM and RIH interneurons uptake 5-HT released from chemosensory neurons and secretory neurons. Genetic analyses suggest that 5-HT secreted by both synaptic vesicles and dense core vesicles diffuse readily to the extrasynaptic space adjacent to the AIM and RIH neurons. Loss of mod-5/SERT function blocks the 5-HT absorption. mod-5/SERT mutants have been shown to exhibit exaggerated locomotor response to food deprivation. We found that transgenic expression of MOD-5/SERT in the 5-HT-absorbing neurons fully corrected the exaggerated behavior. Experiments of cell-specific inhibition of synaptic transmission suggest that the synaptic release of 5-HT from the 5-HT-absorbing neurons is not required for this behavioral modulation. Our data point to the role of 5-HT-absorbing neurons as temporal-spatial regulators of extrasynaptic 5-HT. Regulation of extrasynaptic 5-HT levels by 5-HT-absorbing neurons may represent a fundamental mechanism of 5-HT homeostasis, integrating the activity of 5-HT-producing neurons with distant targets in the neural circuits, and could be relevant to some actions of SSRIs in human.

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“…Fluoxetine blocks the function of SERT/MOD-5, the serotonin (5HT) reuptake transporter (Keowkase et al 2010; Kullyev et al 2010). As seen in Figure 3, the SWIP response phenotype increased in wild-type animals that were pretreated with fluoxetine but decreased in similarly treated dat-1 (ok157) animals.…”

Section: Resultsmentioning

confidence: 99%

Dopamine Signaling inC. elegansIs Mediated in Part by HLH-17-Dependent Regulation of Extracellular Dopamine Levels

Felton

Johnson

2014

G3 Genes|Genomes|Genetics

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In Caenorhabditis elegans, the dopamine transporter DAT-1 regulates synaptic dopamine (DA) signaling by controlling extracellular DA levels. In dat-1(ok157) animals, DA is not taken back up presynaptically but instead reaches extrasynpatic sites, where it activates the dopamine receptor DOP-3 on choligeneric motor neurons and causes animals to become paralyzed in water. This phenotype is called swimming-induced paralysis (SWIP) and is dependent on dat-1 and dop-3. Upstream regulators of dat-1 and dop-3 have yet to be described in C. elegans. In our previous studies, we defined a role for HLH-17 during dopamine response through its regulation of the dopamine receptors. Here we continue our characterization of the effects of HLH-17 on dopamine signaling. Our results suggest that HLH-17 acts downstream of dopamine synthesis to regulate the expression of dop-3 and dat-1. First, we show that hlh-17 animals display a SWIP phenotype that is consistent with its regulation of dop-3 and dat-1. Second, we show that this behavior is enhanced by treatment with the dopamine reuptake inhibitor, bupropion, in both hlh-17 and dat-1 animals, a result suggesting that SWIP behavior is regulated via a mechanism that is both dependent on and independent of DAT-1. Third, and finally, we show that although the SWIP phenotype of hlh-17 animals is unresponsive to the dopamine agonist, reserpine, and to the antidepressant, fluoxetine, hlh-17 animals are not defective in acetylcholine signaling. Taken together, our work suggests that HLH-17 is required to maintain normal levels of dopamine in the synaptic cleft through its regulation of dop-3 and dat-1.

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A Genetic Survey of Fluoxetine Action on Synaptic Transmission in Caenorhabditis elegans

Cited by 48 publications

References 78 publications

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

Regulation of Extrasynaptic 5-HT by Serotonin Reuptake Transporter Function in 5-HT-Absorbing Neurons Underscores Adaptation Behavior in Caenorhabditis elegans

Dopamine Signaling inC. elegansIs Mediated in Part by HLH-17-Dependent Regulation of Extracellular Dopamine Levels

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