Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans

Authors: LIU, HESONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); HE, YANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); LIU, HAILAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); BROUWERS, BAS - UNIVERSITY OF CAMBRIDGE; YIN, NA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); LAWLER, KATHERINE - UNIVERSITY OF CAMBRIDGE; KEOGH, JULIA - UNIVERSITY OF CAMBRIDGE; HENNING, ELANA - UNIVERSITY OF CAMBRIDGE; LEE, DONG-KEE - BAYLOR COLLEGE OF MEDICINE; YU, MENG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); TU, LONGLONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); ZHANG, NAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); CONDE, KRISTINE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); HAN, JUNYING - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); YAN, ZILI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); SCARCELLI, NIKOLAS - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); LIAO, LAN - BAYLOR COLLEGE OF MEDICINE; XU, JIANMING - BAYLOR COLLEGE OF MEDICINE; TONG, QINGCHUN - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER; ZHENG, HUI - BAYLOR COLLEGE OF MEDICINE; SUN, ZHENG - BAYLOR COLLEGE OF MEDICINE; YANG, YONGJIE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); WANG, CHUNMEI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); HE, YANLIN - LOUISIANA STATE UNIVERSITY; FAROOQI, I - UNIVERSITY OF CAMBRIDGE; XU, YONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)

Submitted to: Science Advances
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/22/2024
Publication Date: 6/28/2024
Citation: Liu, H., He, Y., Liu, H., Brouwers, B., Yin, N., Lawler, K., Keogh, J.M., Henning, E., Lee, D., Yu, M., Tu, L., Zhang, N., Conde, K.M., Han, J., Yan, Z., Scarcelli, N.A., Liao, L., Xu, J., Tong, Q., Zheng, H., Sun, Z., Yang, Y., Wang, C., He, Y., Farooqi, I., Xu, Y. 2024. Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans. Science Advances. https://doi.org/10.1126/sciadv.adl2675.
DOI: https://doi.org/10.1126/sciadv.adl2675

Interpretive Summary: This study shows that the serotonin 5-HT2C receptor is important for memory, especially in Alzheimer's disease. Researchers found that mice with a specific mutation in this receptor had poor memory and less flexible brain cells in the hippocampus, a key memory area. Serotonin neurons connect to these hippocampal cells, and disrupting serotonin production or removing the 5-HT2C receptors in this area harmed memory and brain cell flexibility. However, using a drug called lorcaserin, which activates the 5-HT2C receptor, improved memory and brain cell function in an Alzheimer's mouse model. These findings suggest that targeting the 5-HT2C receptor could help treat memory problems in dementia.

Technical Abstract: Declined memory is a hallmark of Alzheimer's disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT2CR) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT2CRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT2CR agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model. Cumulatively, we demonstrate that hippocampal 5-HT2CR signaling regulates memory, which may inform the use of 5-HT2CR agonists in the treatment of dementia.