Spatiotemporal dynamics of 5-HT6 receptor ciliary localization during mouse brain development

• Published in: Neurobiology of disease 2023-01, Vol.176, p.105949-105949, Article 105949
• Main Authors: Dupuy, Vincent, Prieur, Matthieu, Pizzoccaro, Anne, Margarido, Clara, Valjent, Emmanuel, Bockaert, Joël, Bouschet, Tristan, Marin, Philippe, Chaumont-Dubel, Séverine
• Format: Article
• Language: English
• Subjects: Life Sciences; Neurobiology; Neuronal development; Neurons and Cognition; Primary cilium; Serotonin receptor
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2022.105949

The serotonin 5-HT6 receptor (5-HT6R) is a promising target to improve cognitive symptoms of psychiatric diseases of neurodevelopmental origin, such as autism spectrum disorders and schizophrenia. However, its expression and localization at different stages of brain development remain largely unknown, due to the lack of specific antibodies to detect endogenous 5-HT6R. Here, we used transgenic mice expressing a GFP-tagged 5-HT6R under the control of its endogenous promoter (Knock-in) as well as embryonic stem cells expressing the GFP-tagged receptor to extensively characterize its expression at cellular and subcellular levels during development. We show that the receptor is already expressed at E13.5 in the cortex, the striatum, the ventricular zone, and to a lesser extent the subventricular zone. In adulthood, it is preferentially found in projection neurons of the hippocampus and cerebral cortex, in striatal medium-sized spiny neurons, as well as in a large proportion of astrocytes, while it is expressed in a minor population of interneurons. Whereas the receptor is almost exclusively detected in the primary cilia of neurons at embryonic and adult stages and in differentiated stem cells, it is located in the somatodendritic compartment of neurons from some brain regions at the neonatal stage and in the soma of undifferentiated stem cells. Finally, knocking-out the receptor induces a shortening of the primary cilium, suggesting that it plays a role in its function. This study provides the first global picture of 5-HT6R expression pattern in the mouse brain at different developmental stages. It reveals dynamic changes in receptor localization in neurons at the neonatal stage, which might underlie its key role in neuronal differentiation and psychiatric disorders of neurodevelopmental origin. •The 5-HT6R is widely expressed in the brain, from early embryonic to adult stage.•The 5-HT6R is mainly expressed in projection neurons as well as astrocytes.•The 5-HT6R is primarily located in the primary cilium of neurons and astrocytes.•The 5-HT6R relocalizes to the soma membrane at the neonatal stage.•This dynamic change may underlie key roles of the receptor in neurodevelopment.