5-HT(6) receptor blockade regulates primary cilia morphology in striatal neurons
Open accessAbstract
The 5-HT 6 receptor has been implicated in a variety of cognitive processes including habitual behaviors, learning, and memory. It is found almost exclusively in the brain, is expressed abundantly in striatum, and localizes to neuronal primary cilia. Primary cilia are antenna-like, sensory organelles found on most neurons that receive both chemical and mechanical signals from other cells and the surrounding environment; however, the effect of 5-HT 6 receptor function on cellular morphology has not been examined. We confirmed that 5-HT 6 receptors were localized to primary cilia in wild-type (WT) but not 5-HT 6 knockout (5-HT 6 KO) in both native mouse brain tissue and primary cultured striatal neurons then used primary neurons cultured from WT or 5-HT 6 KO mice to study the function of these receptors. Selective 5-HT 6 antagonists reduced cilia length in neurons cultured from wild-type mice in a concentration and time-dependent manner without altering dendrites, but had no effect on cilia length in 5-HT 6 KO cultured neurons. Varying the expression levels of heterologously expressed 5-HT 6 receptors affected the fidelity of ciliary localization in both WT and 5-HT 6 KO neurons; overexpression lead to increasing amounts of 5-HT 6 localization outside of the cilia but did not alter cilia morphology. Introducing discrete mutations into the third cytoplasmic loop of the 5-HT 6 receptor greatly reduced, but did not entirely eliminate, trafficking of the 5-HT 6 receptor to primary cilia. These data suggest that blocking 5-HT 6 receptor activity reduces the length of primary cilia and that mechanisms that regulate trafficking of 5-HT 6 receptors to cilia are more complex than previously thought.
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In cultured mouse striatal neurons, treatment with SB-399885 (5-HT6 receptor antagonist) shortens primary cilia with no impact on their ciliation, and this effect is absent in striatal neurons from 5-HT6KO, demonstrating that the drug's effect is dependent on the presence of the receptor on the primary cilium.
“In cultured mouse striatal neurons, treatment with SB-399885 (5-HT6 receptor antagonist) shortened primary cilia with no impact on their ciliation. Crucially, this effect is absent in striatal neurons from 5-HT6KO, demonstrating that the drug’s effect is dependent on the presence of the receptor on the primary cilium.”
From Primary cilia in the mature brain: emerging roles in Alzheimer's disease pathogenesis (2025) · cites this paper as Brodsky et al., 2017
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Experimental — accuracy not yet measuredHigh levels of heterologous 5-HT6 receptor expression increase the receptor's presence outside of the primary cilia without altering the morphology of the primary cilia.
“High levels of heterologous 5-HT6 receptor expression increased the receptor’s presence outside of the primary cilia without altering the morphology of the primary cilia (Brodsky et al., 2017).”
From Primary cilia in the mature brain: emerging roles in Alzheimer's disease pathogenesis (2025) · cites this paper as Brodsky et al., 2017
Treatment with WAY-208466 (5-HT6 receptor agonist) does not affect primary cilia length in cultured mouse striatal neurons.
“Treatment with WAY-208466 (5-HT6 receptor agonist) did not affect primary cilia length in cultured mouse striatal neurons (Brodsky et al., 2017).”
From Primary cilia in the mature brain: emerging roles in Alzheimer's disease pathogenesis (2025) · cites this paper as Brodsky et al., 2017
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- Authors
- Brodsky, M., Lesiak, A. J., Croicu, A., Cohenca, N., Sullivan, J. M., & Neumaier, J. F.
- Affiliations
- University of Washington (US)
- Corresponding author
- Neumaier, John F.
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 1660
- Pages
- 10-19
- ISSN
- 0006-8993 (ISSN-L)
- PMC
- PMC5392252
- OpenAlex
- W2576623657
- Cited by
- 54
- References
- 74
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 1 · 2023: 6 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 5 · 2018: 5 · 2017: 1
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIDA (T32-DA00007278, R01 DA030807, R21 DA035577)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- 5-HT6 receptor, serotonin receptors, primary cilia, cilia length, striatal neurons, receptor trafficking, receptor localization, receptor overexpression, receptor antagonists
- MeSH terms
- Animals, Cells, Cultured, Cilia, Corpus Striatum, Dose-Response Relationship, Drug, Methylamines, Mice, Inbred C57BL, Neurons, Piperazines, Pyridines, Receptors, Serotonin, Serotonin Antagonists, Sulfonamides, Time Factors, Gene Expression, Serotonin Receptor Agonists, Mice, Knockout
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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