Neural Circuits Expressing the Serotonin 2C Receptor Regulate Memory in Mice and Humans

Authors

Hesong Liu
Yang He
Hailan Liu
Bas Brouwers
Na Yin
Katherine Lawler
Julia M Keogh
Elana Henning
Dong-Kee Lee
Meng Yu
Longlong Tu
Nan Zhang
Kristine M Conde
Junying Han
Zili Yan
Nikolas A Scarcelli
Lan Liao
Jianming Xu
Qingchun Tong
Hui Zheng
Zheng Sun
Yongjie Yang
Chunmei Wang
Yanlin He
I Sadaf Farooqi
Yong Xu

Publication Date

6-28-2024

Journal

Science Advances

DOI

10.1126/sciadv.adl2675

PMID

38941473

PMCID

PMC11212768

PubMedCentral® Posted Date

6-28-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Humans, Receptor, Serotonin, 5-HT2C, Memory, Mice, Mice, Transgenic, Neuronal Plasticity, Alzheimer Disease, Hippocampus, Serotonin, Disease Models, Animal, CA1 Region, Hippocampal, Neurons, Serotonin 5-HT2 Receptor Agonists

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.