5-HT 6 receptor blockade regulates primary cilia morphology in striatal neurons.

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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