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

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• The serotonin 5-HT₆ receptor (5-HT₆R) is a potential therapeutic target for cognitive deficits in neurodevelopmental disorders like autism and schizophrenia.
• Understanding 5-HT₆R expression and localization during brain development is crucial but limited by the lack of specific antibodies for endogenous detection.

Purpose of the Study:

• To characterize the expression pattern and subcellular localization of the 5-HT₆ receptor throughout mouse brain development.
• To investigate the role of 5-HT₆R in primary cilia function.

Main Methods:

• Utilized transgenic mice expressing a GFP-tagged 5-HT₆R under its endogenous promoter (knock-in model).
• Examined receptor expression in embryonic stem cells and various brain regions at different developmental stages (embryonic, neonatal, adult).
• Investigated the effect of 5-HT₆R knockout on primary cilia structure.

Main Results:

• 5-HT₆R is expressed early in development (E13.5) in cortical and striatal regions.
• In adults, the receptor is found in projection neurons, medium-sized spiny neurons, and astrocytes, with limited expression in interneurons.
• Receptor localization shifts dynamically: primarily in primary cilia in embryonic/adult stages, but also in somatodendritic compartments and cell soma during neonatal stages and in stem cells.

Conclusions:

• This study provides the first comprehensive map of 5-HT₆R expression and localization across mouse brain development.
• Dynamic neonatal localization suggests a role for 5-HT₆R in neuronal differentiation.
• 5-HT₆R knockout leads to primary cilium shortening, indicating a functional role in cilia biology relevant to neurodevelopmental disorders.