Researchers headed by teams at Baylor College of Medicine and the University of Cambridge have shown that the serotonin 2C receptor in the brain regulates memory in people and animal models. Their study findings provide new insights into the factors involved in healthy memory and in disorders, such as Alzheimer’s disease (AD), associated with memory loss. The results also point to potential avenues for AD therapy using serotonin analogs.

The team reported on the findings in Science Advances, in a paper titled, “Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans.”

Memory deficits are a hallmark of Alzheimer’s disease, and studies in rodents and in postmortem human tissues have suggested that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, the authors wrote. “However, the mechanisms by which serotonin regulates working memory are largely unknown.”

Co-corresponding author Yong Xu, MD, PhD, professor of pediatrics—nutrition and associate director for basic sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor, explained further: “Serotonin, a compound produced by neurons in the midbrain, acts as a neurotransmitter, passing messages between brain cells … 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 a certain activity. For their newly reported study the Xu lab, which has expertise in basic and genetic animal studies, and the human genetics lab of co-corresponding author I. Sadaf Farooqi, FMedSci FRS, professor of metabolism and medicine at the University of Cambridge, focused on serotonin 2C receptors, which are abundantly present in the brain’s ventral hippocampal CA1 region (vCA1), investigating the role of the receptor 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. These variants resulted in loss of function (LOF). The authors further noted, “… five young women (22 to 29 years) carrying rare LOF HTR2C mutations completed the Prospective-Retrospective Memory Questionnaire (PRMQ) (21), and all reported remarkable impact on prospective and retrospective memory.”

Farooqi continued, “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 the human mutation. “The potential association between HTR2C variants and memory deficits observed in humans prompted us to use a humanized Htr2c mutant mouse model to further examine the causality,” they noted. When the researchers ran behavioral tests on these mice to evaluate their memory, they found that both males and females with the non-functional gene showed reduced memory recall when compared with the unmodified animals.

“When we combined the human data and the mouse data, we found compelling evidence connecting non-functional mutations of the serotonin receptor 2C with memory deficits in humans,” Xu said.

The animal models also enabled the team to dig deeper into how the receptor mediates memory. They discovered a brain circuit that begins in the midbrain where serotonin-producing neurons are located. These neurons project to the vCA1 region, which has abundant serotonin 2C receptors. “When neurons in the midbrain reaching out to neurons in the vCA1 region release serotonin, the neurotransmitter binds to its receptor signaling these cells to make changes that help the brain consolidate memories,” Xu said.

The authors further stated, “These data demonstrate that the 5-HT2CR signaling in hippocampal vCA1 neurons is required for normal learning and memory … We show that mice carrying a severe LOF human HTR2C mutation have impaired memory and impaired plasticity of hippocampal vCA1 neurons.”

Importantly, the researchers also found that this serotonin-associated neural circuit is damaged in a mouse model of AD. “The neural circuit in the Alzheimer’s disease animal model cannot release sufficient serotonin into the vCA1 region that would need to bind to its receptor in the downstream neurons to signal the changes required to consolidate a memory,” Xu said. “We show that a selective 5-HT2CR agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model,” the authors stated. “While there is no evidence yet linking HTR2C gene variants with AD, reduced brain 5-HT bioavailability has been observed in the brains of patients with AD,” the team stated. “Several studies have reported a decreased number of 5-HT neurons and reduced levels of 5-HT and its metabolites in the brains of patients with AD.

However, it is possible to bypass this lack of serotonin and directly activate the downstream serotonin receptor by administering a serotonin analog, lorcaserin, a compound that selectively activates the serotonin 2C receptor in these cells. “We tested this strategy in our animal model and were excited to find that the animals treated with the serotonin analog improved their memory,” Xu said. “We hope our findings encourage further studies to evaluate the value of serotonin analogs in the treatment of Alzheimer’s disease.”

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