5‐HT6R null mutatrion induces synaptic and cognitive defects

• Published in: Aging cell Vol. 20; no. 6; pp. e13369 - n/a
• Main Authors: Sun, Zehui, Wang, Bingjie, Chen, Chen, Li, Chenjian, Zhang, Yan
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-06-2021; John Wiley and Sons Inc
• Subjects: 5‐HT6R; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Animal behavior; Animals; Anxiety; Biogenic amines; Central nervous system; Cilia; Cognition & reasoning; Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Disease Models, Animal; Emotional disorders; Excitability; Hedgehog protein; learning and memory; Memory; Mental disorders; Mice; Mice, Inbred C57BL; Mood disorders; Morphology; Motor ability; Neurodegenerative diseases; neuronal excitability; Neurophysiology; Original; Original Paper; Pathogenesis; Physiological aspects; primary cilia; Receptors, Serotonin - deficiency; Receptors, Serotonin - genetics; Receptors, Serotonin - metabolism; Rodents; Schizophrenia; Signal transduction; Synapses - genetics; Synapses - metabolism; Synapses - pathology; Velocity; learning and memory; 5-HT6R; primary cilia; neuronal excitability
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13369

Serotonin 6 receptor (5‐HT6R) is a promising target for a variety of human diseases, such as Alzheimer's disease (AD) and schizophrenia. However, the detailed mechanism underlying 5‐HT6R activity in the central nervous system (CNS) is not fully understood. In the present study, 5‐HT6R null mutant (5‐HT6R−/−) mice were found to exhibit cognitive deficiencies and abnormal anxiety levels. 5‐HT6R is considered to be specifically localized on the primary cilia. We found that the loss of 5‐HT6R affected the Sonic Hedgehog signaling pathway in the primary cilia. 5‐HT6R−/− mice showed remarkable alterations in neuronal morphology, including dendrite complexity and axon initial segment morphology. Neurons lacking 5‐HT6R exhibited increased neuronal excitability. Our findings highlight the complexity of 5‐HT6R functions in the primary ciliary and neuronal physiology, supporting the theory that this receptor modulates neuronal morphology and transmission, and contributes to cognitive deficits in a variety of human diseases, such as AD, schizophrenia, and ciliopathies.
Alzheimer’s disease (AD) is associated with changesin synaptic morphology, nervous system dysfunction, and cognitive decline. Lossof 5‐HT6R elevates anxiety and decreases learning and memory ability in mice.Meanwhile, changes in ciliary signaling, dendrites, synaptic plasticity, andneuronal excitability are found in 5‐HT6R mutant mice, suggesting that5‐HT6R has potential therapeutic value in impeding AD progression.