Serotonin Signaling Necessary for Memory Function is Lost in Alzheimer's Disease

Alzheimer's disease is a very complex condition, as the brain is a very complex organ. Researchers here show that the many pathological dysfunctions in Alzheimer's disease include a disruption to serotonin signaling that inhibits memory consolidation. Since this is a problem of too little serotonin interacting with serotonin receptors necessary for function, it is possible in principle to deliver small molecule receptor agonist drugs to compensate for this loss. The challenge lies in delivering the right amount of receptor stimulation to the right places, as undesirable side-effects will arise from too much receptor stimulation in the wrong places. This is the present mainstream of drug development in a nutshell: ignore root causes, attempt to compensate for one specific undesirable pathological consequence of those root causes, and struggle to find an acceptable compromise between dose, benefit, targeting, and side-effects.

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. "We had previously identified five individuals carrying variants of the serotonin 2C receptor gene (HTR2C) that produce defective forms of the receptor. 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 animal models enabled researchers 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 ventral CA1 (vCA1) region of the hippocampus, 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." Importantly, the researchers also found that this serotonin-associated neural circuit is damaged in a mouse model of Alzheimer's disease. "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."

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. We hope our findings encourage further studies to evaluate the value of serotonin analogs in the treatment of Alzheimer's disease."

Link: https://www.bcm.edu/news/serotonin-2c-receptor-regulates-memory-in-mice-and-humans-implications-for-alzheimers-disease