Melatonin enhances long-term memory by modulating protein phosphorylation

Multiple studies have demonstrated the memory-enhancing effects of melatonin and its derivatives in animal models. Additionally it is known that the formation of each short- and long-term memories require the phosphorylation of certain memory-related proteins. Nevertheless, the molecular mechanisms underlying melatonin-induced memory enhancement have remained elusive. Now, medical researchers from Sophia University, Japan, have made vital findings that contribute significantly to the elucidation of the underlying mechanisms in a recent article that was made available online on 10 May 2023 and published in Volume 34 Issue 9 of NeuroReport on 7 June 2023.

Regarding the premise of the study, lead creator Professor Atsuhiko Chiba from the Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, says, “Our study aimed to research the results of melatonin, ramelteon, and N1-acetyl-5-methoxyquinuramine on the relative phosphorylation levels of memory-related proteins with the intention to explore candidate signaling pathways related to the receptor- and nonreceptor-mediated memory-enhancing effects of melatonin.”

In simpler terms, the research team, which included Dr. Masahiro Sano (currently affiliated with Tohoku University) and Dr. Hikaru Iwashita (currently affiliated with Kansai Medical University), examined the results of three compounds on memory formation; these compounds were melatonin, a hormone secreted by the pineal gland situated within the brain; N1-acetyl-5-methoxyquinuramine (AMK), melatonin’s biological metabolite; and ramelteon, a drug that binds and prompts the melatonin receptor. As well as, they examined “phosphorylation,” or the biochemical addition of phosphate groups to protein structures, in five key proteins involved in memory formation. These included the protein extracellular signal-regulated kinase (ERK), calcium/calmodulin-dependent kinase IIα (CaMKIIα), CaMKIIβ, CaMKIV, and the cAMP-response element binding protein (CREB).

Initial experiments conducted on male mice clearly showed that the administration of melatonin, ramelteon, or AMK at a dose of 1 mg/kg facilitated the formation of long-term memory. The researchers didn’t investigate the results of the three compounds on female mice to avoid any likely data variability resulting from the reproductive cycles occurring in female mammals.

Long-term memory formation in male mice was assessed by conducting a series of experiments based on the novel objection recognition task or “NORT.” On this study, laboratory mice under investigation were first acclimated to an experimental arena for five minutes per day for 3 consecutive days. On the fourth day, two an identical objects were placed within the experimental arena and mice were allowed to explore these objects for five minutes (training phase). Twenty-four hours after the cessation of the training phase, the male mice were subjected to testing. Through the testing phase, one out of the 2 familiar objects was replaced with a brand new or unfamiliar object. The period of time spent by the mice exploring each object-;a great measure of object recognition memory-;was recorded by a trained observer. It’s a known proven fact that mice spend more time exploring novel objects they encounter and fewer near familiar objects.

The researchers then studied the results of ramelteon and AMK on the phosphorylation of ERK, CaMKIIα, CaMKIIβ, CaMKIV, and CREB within the male mouse brain after sacrificing the rodents using standard protocols. Within the hippocampus, which is the training and memory center of the mammalian brain, treatment with ramelteon/AMK significantly increased the phosphorylation of each ERK and CREB. Nevertheless, these drugs significantly decreased CaMKIIα/β phosphorylation in the identical brain region. Within the perirhinal cortex (PRC), which can be related to memory functions, each ramelteon and AMK significantly increased ERK, and only ramelteon significantly increased CaMKIIβ phosphorylation. Within the hippocampus/PRC, ramelteon/AMK didn’t affect the phosphorylation of CaMKIV.

Talking in regards to the study’s results, Prof. Chiba concludes, “Our findings suggest that melatonin is involved in promoting the formation of long-term object recognition memory by modulating the phosphorylation levels of memory-related proteins similar to ERK, CaMKIIs, and CREB in each receptor-mediated and nonreceptor-mediated signaling pathways.”

What implications could these study findings have on humans? The researchers consider that the outcomes of their study will contribute to the event of latest drugs that may improve memory function in people affected by age-related memory impairment with fewer unwanted effects. For a steadily ageing global society, that is indeed a remarkable discovery!