Summary: Researchers have identified the serotonin 2C receptor in the brain as a key regulator of memory in both humans and animal models. This discovery sheds light on mechanisms behind memory decline in disorders like Alzheimer’s disease and points toward new therapeutic approaches.
Mutations in the gene that encodes the serotonin 2C receptor (HTR2C) are associated with memory impairments, while selective serotonin 2C receptor agonists such as lorcaserin can restore memory performance in experimental models. These results highlight the receptor as a potential target for treating memory-related conditions.
Key Facts:
- Serotonin 2C receptors play a central role in memory consolidation.
- Variants in the HTR2C gene can produce defective receptors and are linked to memory deficits.
- Selective serotonin 2C receptor agonists can improve synaptic plasticity and memory in Alzheimer’s disease models.
Source: Baylor College of Medicine
Overview of the research
A team of researchers from Baylor College of Medicine, the University of Cambridge and collaborating institutions has shown that neural circuits expressing the serotonin 2C receptor regulate memory in humans and mice. Their findings, published in Science Advances, advance understanding of how serotonin signaling supports healthy memory and how its dysfunction contributes to memory loss in neurodegenerative disorders.
“Serotonin, produced by neurons in the midbrain, acts as a neurotransmitter that transmits signals between brain cells,” said Dr. Yong Xu, co-corresponding author and professor of pediatrics – nutrition at Baylor College of Medicine. “Serotonin-producing neurons send projections to multiple brain areas, including the hippocampus, which is essential for forming and retrieving memories.”
The research teams combined human genetic studies and detailed animal experiments to focus on the serotonin 2C receptor (5-HT2C receptor), which is highly expressed in the ventral hippocampal CA1 region (vCA1). Prior genetic screening identified five individuals who carry HTR2C variants that produce nonfunctional receptor proteins. Those individuals reported significant memory problems on clinical questionnaires, prompting deeper investigation in controlled models.
To model the human genetic variants, scientists engineered mice carrying the same HTR2C mutation. Behavioral testing showed that these mice—both male and female—displayed impaired memory recall compared with wild-type controls. Combining the human and mouse data provided strong evidence that loss-of-function mutations in the serotonin 2C receptor contribute to memory deficits.
Using the mouse models, the team mapped a specific circuit: serotonin-producing neurons in the midbrain send axonal projections directly to vCA1 neurons that express abundant 5-HT2C receptors. When serotonin is released at these synapses, it binds to 5-HT2C receptors on vCA1 neurons and triggers cellular changes that support synaptic plasticity and memory consolidation.
Importantly, the researchers found that this serotonin-linked circuit is disrupted in a mouse model of Alzheimer’s disease. In that model, midbrain neurons fail to release sufficient serotonin into the vCA1 region, preventing adequate activation of 5-HT2C receptors and impairing the synaptic changes needed to form stable memories.
To bypass reduced serotonin release, investigators tested a pharmacological approach: administering lorcaserin, a selective 5-HT2C receptor agonist. Treating the Alzheimer’s model mice with lorcaserin directly activated downstream receptors in vCA1 and improved measures of synaptic plasticity and memory performance in behavioral assays.
“Our results show that targeted activation of 5-HT2C receptors can restore memory-related plasticity in an Alzheimer’s disease model,” Dr. Xu said. “These findings support further study of 5-HT2C receptor agonists as a potential therapeutic avenue for dementia and other memory disorders.”
The study involved many contributors from Baylor College of Medicine, Texas Children’s Hospital, the University of Cambridge, the University of Texas Health Science Center at Houston, and Louisiana State University. Key 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 and Yanlin He.
About this study
Author: Taylor Barnes
Source: Baylor College of Medicine
Contact: Taylor Barnes – Baylor College of Medicine
Image credit: Neuroscience News
Original Research: Open access. “Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans” by Yong Xu et al., published in Science Advances.
Abstract (summary)
Memory decline is a core feature of Alzheimer’s disease. Prior studies in animals and human tissues have implicated serotonin (5-hydroxytryptamine, 5-HT) in memory, but the precise mechanisms were unclear. This research examines the role of the 5-HT2C receptor in memory regulation. Transgenic mice carrying a human HTR2C mutation showed impaired plasticity in ventral CA1 hippocampal neurons and reduced memory. Serotonergic neurons project to and form synapses on vCA1 neurons; disrupting serotonin synthesis in those projecting neurons or deleting 5-HT2C receptors in vCA1 impairs synaptic plasticity and memory. A selective 5-HT2C receptor agonist, lorcaserin, improved synaptic function and memory in an Alzheimer’s disease mouse model. Together, these findings demonstrate that hippocampal 5-HT2C receptor signaling regulates memory and support exploration of 5-HT2C receptor agonists as potential treatments for dementia.