PT  - JOURNAL ARTICLE
AU  - Atom J. Lesiak
AU  - Matthew Brodsky
AU  - Nathalie Cohenca
AU  - Alexandra G. Croicu
AU  - John F. Neumaier
TI  - Restoration of physiological expression of 5-HT6 into the primary cilia of null mutant neurons lengthens both primary cilia and dendrites.
AID  - 10.1124/mol.117.111583
DP  - 2018 Jan 01
TA  - Molecular Pharmacology
PG  - mol.117.111583
4099  - http://molpharm.aspetjournals.org/content/early/2018/04/20/mol.117.111583.short
4100  - http://molpharm.aspetjournals.org/content/early/2018/04/20/mol.117.111583.full
AB  - 5-HT6 serotonin receptors are promising targets for a variety of neuropsychiatric disorders and have been linked to several cellular signaling cascades. Endogenous 5-HT6 receptors are restricted to the primary neuronal cilium, a small sensory organelle stemming from the cell body that receives numerous extra-synaptic signals. Inhibition of 5-HT6 receptors decreases cilia length in primary neuronal cultures, but the signaling mechanisms involved are still unclear. Intense overexpression of exogenous 5-HT6 receptors increases the likelihood for receptors to localize outside of 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-HT6R rescue on neuronal morphology in primary neuronal cultures from 5-HT6R-KO mice, while maintaining a more physiological level of expression, wherein the receptor localizes to cilia in 80-90% of neurons (similar to endogenous 5-HT6R localization). We found that rescue of 5-HT6R 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-HT6R mutants, deficient in agonist-stimulated cAMP or without the predicted Fyn kinase binding domain, maintain constitutive activity for stimulating cAMP and still increased the length of cilia, while the proposed Fyn kinase domain was required for stimulating dendritic outgrowth. These findings highlight the complexity of 5-HT6R function and localization, particularly when using exogenous overexpression, and provide greater understanding and potential mechanisms for 5-HT6R drug therapies.