Researchers at Baylor College of Medicine, the University of Cambridge in the U.K., and collaborating institutions have demonstrated that the serotonin 2C receptor in the brain regulates memory in both humans and animal models. The findings, published in the journal Science Advances, provide new insights into factors involved in healthy memory and conditions associated with memory loss, such as Alzheimer’s disease. These results suggest potential novel avenues for treatment.
“Serotonin, a compound produced by neurons in the midbrain, acts as a neurotransmitter, passing messages between brain cells,” said Dr. Yong Xu, professor of pediatrics – nutrition and associate director for basic sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor. “Serotonin-producing neurons reach out to multiple brain regions including the hippocampus, a region essential for short- and long-term memory.”
Serotonin communicates messages to brain cells by binding to receptors on the cell surface, which signal the receiving cell to carry on certain activities. In this study, Xu's lab collaborated with Dr. I. Sadaf Farooqi's human genetics lab at the University of Cambridge to focus on serotonin 2C receptors present abundantly in the brain's ventral hippocampal CA1 region (vCA1). They investigated this receptor's role in memory in humans and animal models.
“We had previously identified five individuals carrying variants of the serotonin 2C receptor gene (HTR2C) that produce defective forms of the receptor,” Farooqi said. “People with these rare variants showed significant deficits on memory questionnaires. These findings led us to investigate the association between HTR2C variants and memory deficits in animal models.”
The team genetically engineered mice to mimic human mutations. Behavioral tests on these mice revealed that those with non-functional genes exhibited reduced memory recall compared to unmodified animals. “When we combined the human data and mouse data, we found compelling evidence connecting non-functional mutations of serotonin receptor 2C with memory deficits in humans,” Xu said.
The animal models enabled further investigation into how this receptor mediates memory. The researchers discovered a brain circuit beginning in the midbrain where serotonin-producing neurons are located; these neurons project to vCA1 region abundant with serotonin 2C receptors.
“When neurons in the midbrain reaching out to neurons in vCA1 release serotonin, it binds to its receptor signaling these cells to make changes that help consolidate memories,” Xu explained.
Importantly, they found this neural circuit is damaged in an Alzheimer's disease mouse model. “The neural circuit cannot release sufficient serotonin into vCA1 needed for binding its receptor downstream to signal required changes for consolidating a memory,” Xu noted.
However, bypassing this lack of serotonin by directly activating downstream receptors using lorcaserin—a compound selectively activating serotonin 2C receptors—showed promise. "We tested this strategy and found treated animals improved their memory," Xu said. "We hope our findings encourage further studies evaluating serotonin analogs' value for treating Alzheimer’s disease."
Contributors include 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 Affiliations: Baylor College of Medicine Texas Children’s Hospital University of Cambridge University of Texas Health Science Center Houston Louisiana State University See publication sources financial support work
