Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer's disease by regulating cilia function

Background: Serotonin receptor 5-HT6 is involved in cognition and Alzheimer's disease (AD) development. However, the mechanism of 5-HT6 in AD pathology is not clear. Methods: Since 5-HT6 is almost exclusively expressed in the primary cilia, using immunostaining we examined the number of cilia in the hippocampus of AD animal model APP/PS1 mice. By overexpressing and knocking down 5-HT6 in the primary cultured hippocampal neurons, we investigated the roles of 5-HT6 in alternating ciliary morphology. Furthermore, 5-HT6 antagonist was applied to confirm its roles in cognition using the Morris water maze test, Y maze, and fear conditioning. Results: In the present study, we found that the primary cilia were elongated in the hippocampus of APP/PS1 mice compared with WT mice. 5-HT6 regulated cilia length, influenced cilia and axon initial segment (AIS) morphology, and affected localization of ARL13B and AnkG. We also found that, by changing cilia morphology, the AIS was elongated, branched, and more proximal to the cell body in both WT and APP/PS1 mouse neurons. Alterations of cilia also decreased the axonal length in WT and APP/PS1 neurons. Furthermore, in the water maze test, Y maze, and fear conditioning test, 5-HT6 antagonist SB271046 recovered the cognitive impairment of APP/PS1 mice. Conclusion: We suggest that 5-HT6 plays a critical role in AD development through regulating the morphology and function of neuronal primary cilia, which is possibly related to the AIS and axon alterations in AD development.