Restoration of Physiological Expression of 5-HT6 Receptor into the Primary Cilia of Null Mutant Neurons Lengthens Both Primary Cilia and Dendrites
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5-HT 6 (serotonin) receptors are promising targets for a variety of neuropsychiatric disorders and have been linked to several cellular signaling cascades. Endogenous 5-HT 6 receptors are restricted to the primary neuronal cilium, a small sensory organelle stemming from the cell body that receives numerous extrasynaptic signals. Inhibition of 5-HT 6 receptors decreases cilia length in primary neuronal cultures, but the signaling mechanisms involved are still unclear. Intense overexpression of exogenous 5-HT 6 receptors increases the probability for receptors to localize outside the primary cilium and have been associated with changes in cilia morphology and dendritic outgrowth. In the present study, we explore the role of 5-HT 6 R rescue on neuronal morphology in primary neuronal cultures from 5-HT 6 R-KO mice, at the same time maintaining a more physiologic level of expression, wherein the receptor localizes to cilia in 80%-90% of neurons (similar to endogenous 5-HT 6 R localization). We found that rescue of 5-HT 6 R expression is sufficient to increase cilia length and dendritic outgrowth, but primarily in neurons in which the receptor is located exclusively in the primary cilia. Additionally, we found that expression of 5-HT 6 R mutants deficient in agonist-stimulated cAMP or without the predicted Fyn kinase binding domain maintained constitutive activity for stimulating cAMP and still increased the length of cilia, and that the proposed Fyn kinase domain was required for stimulating dendritic outgrowth. These findings highlight the complexity of 5-HT 6 R function and localization, particularly with the use of exogenous overexpression, and provide greater understanding and potential mechanisms for 5-HT 6 R drug therapies.
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In primary striatal neurons from 5-HT6KO mice, reintroduction of 5-HT6 receptors restores their primary ciliary localization without altering the overall ciliation rate, leads to elongation of neuronal primary cilia, and significantly increases the average total dendritic length.
“In primary striatal neurons from 5-HT6KO mice, reintroduction of 5-HT6 receptors restored their primary ciliary localization without altering the overall ciliation rate, led to elongation of neuronal primary cilia, and significantly increased the average total dendritic length (Lesiak et al., 2018).”
From Primary cilia in the mature brain: emerging roles in Alzheimer's disease pathogenesis (2025) · cites this paper as Lesiak et al., 2018
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5-HT6R null mutatrion induces synaptic and cognitive defects
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Primary cilia in the mature brain: emerging roles in Alzheimer's disease pathogenesis
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- Authors
- Lesiak, A. J., Brodsky, M., Cohenca, N., Croicu, A. G., & Neumaier, J. F.
- Affiliations
- University of Washington (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 94
- Issue
- 1
- Pages
- 731-742
- ISSN
- 0026-895X (ISSN-L)
- PMC
- PMC5987994
- OpenAlex
- W2800678646
- Cited by
- 37
- References
- 59
- Citations by year
- 2025: 7 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 1
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Washington State University
- National Institutes of Health
- National Institute on Drug Abuse (R21DA035577, 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 › Neuroscience and Neuropharmacology Research
- Keywords
- 5-HT6 receptor, serotonin receptors, primary cilia, cilia length, dendritic outgrowth, neuronal morphology, receptor overexpression, cAMP signaling, constitutively active receptor mutants
- MeSH terms
- Cyclic AMP, Animals, Cell Line, Cilia, Dendrites, Mice, Inbred C57BL, Neurons, Protein Binding, Receptors, Serotonin, Signal Transduction, Mice, Knockout, Mice
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