New evidence linking serotonin and memory

lab animal Research highlights Memory https://doi.org/10.1038/s41684-024-01423-1 New evidence linking serotonin and memory Check for updates Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter primarily synthesized by neurons in the midbrain; these neurons project to multiple brain regions including the hippocampus, which is associated with memory. Although increasing evidence indicates that 5-HT contributes to memory formation, little is known about the underlying mechanisms. A new study combining the use of genetic mouse models, behavioral tests, electrophysiology and tracing techniques demonstrates the role of 5-HT2C receptor (5-HT2CR) in the regulation of memory in mice. In a previous study, the researchers had identified individuals carrying rare loss-of-function (LOF) variants in HTR2C, encoding 5-HT2CR. When the team observed that the individuals showed significant deficits on memory questionnaires, they decided to further investigate the link between HTR2C variants and memory deficits in mice. Using a CRISPR approach, they introduced a severe LOF human HTR2C mutation in the mouse genome and submitted the mice to a series of behavioral tests, which revealed that mutant mice had learning and memory deficits compared with wild-type (WT) animals. When examining the neural basis for the observed impairment in memory, the researchers found that the 5-HT2CR agonist, lorcaserin, activated most hippocampal ventral CA1 (vCA1) neurons from WT mice, but had no effect in mutant mice. Further analysis revealed that long-term potentiation (LTP) — a form of synaptic plasticity — in the vCA1 was blunted in mutant mice compared to WT mice, indicating that 5-HT2CR signaling regulates LTP in vCA1 neurons. Next, using circuit mapping and neurotracing experiments, the investigators showed that midbrain 5-HT neurons project to and activate vCA1 neurons, revealing the existence of a 5-HT–vCA1 circuit. By using additional mouse models, including mice in which the 5-HT–vCA1 circuit was chemogenetically inhibited, and subjecting them to memory tests, the researchers confirmed the importance of 5-HT/ 5-HT2CR signals in vCA1 neural plasticity and memory formation. Finally, the researchers showed that the 5-HT–vCA1 circuit was damaged in a mouse model of Alzheimer’s disease with known memory deficits. Administration of lorcaserin restored impaired vCA1 neural plasticity and improved memory in these mice. By demonstrating the role of 5-HT2CR signaling in the regulation of memory, these findings may inform the use of 5-HT2CR agonists in the treatment of dementia. Alexandra Le Bras Original reference: Liu, H. et al. Sci. Adv. 10, eadl2675 (2024) The best from Nature’s journalists and other publications worldwide. Always balanced, never oversimplifed, and crafted with the scientific community In mind. Sign up now go.nature.com/briefing A111250 Lab Animal | Volume 53 | August 2024 | 195 195  (...truncated)