By Ilaria Barone, Nicole Gilette, and Jonathan Lipton

Cartoon of a synaptic circadian clock. Image by Engie Mostafa.

Our bodies are synchronized with the earth’s light/dark cycle through a timekeeping mechanism called the circadian clock. This clock is a molecular machine that anticipates the predictable rhythm of the environment and readies almost all of our cells for the changes that will occur. As a result, many aspects of our physiology, including cognition, have different functions depending on the time of day. Learning and memory, for example, requires the brain to respond to and change in response to the environment and to develop paths for retrieving this new information. The brain encodes this information in computational units called synapses, sites of communication between brain cells. The process by which synapses change in response to new information is called synaptic plasticity. But how circadian rhythms impact the function of synapses or synaptic plasticity is unknown. We have discovered that the circadian timekeeping protein BMAL1 is found at synapses in the hippocampus, a region of the brain crucial to memory. The amount of synapse-localized BMAL1 demonstrates a rhythm aligned with the light/dark cycle and it biochemically, spatially, and functionally interacts with critical synaptic organizing proteins. We find that these interactions of BMAL1 with key synaptic proteins are essential to regulate rhythms of synaptic plasticity. Therefore, our discovery suggests that the brain contains information about the time of day at synapses, offering a mechanism by which circadian information can regulate computations with anticipation of the environment. Both circadian rhythms and memory are disrupted in many neurological disorders like Alzheimer’s disease and schizophrenia, thus our findings could provide a novel basis on which future therapies target these disorders.

Ilaria Barone was a post-doctoral fellow in the Lipton laboratory and now is a Group Leader at the University of Milan.
Nicole Gilette is a PhD candidate in the Lipton laboratory and a member of the HMS Graduate Program in Neuroscience and the Harvard-MIT MD/PhD program.
Jonathan Lipton is a PI in the Boston Children’s Hospital Kirby Center for Neurobiology.

This work was funded in part by the HBI Bipolar Disorder Seed Grant program as well as the NIH, DoD, Tuberous Sclerosis Alliance, and a Kirby Innovation Pilot Award.

Learn more in the original research article:
Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity.
Barone I, Gilette NM, Hawks-Mayer H, Handy J, Zhang KJ, Chifamba FF, Mostafa E, Johnson-Venkatesh EM, Sun Y, Gibson JM, Rotenberg A, Umemori H, Tsai PT, Lipton JO. Sci Adv. 2023 Oct 27;9(43): Epub 2023 Oct 25.