The failure of multiple Alzheimer’s disease (AD) clinical trials highlights the need for early markers that accurately identify individuals at risk during the pre-clinical stage before they develop severe symptoms. Within the last decade, spatial navigation deficits have recently emerged as one of the most sensitive behavioral markers of early AD – patients are frequently disoriented and have trouble navigating familiar environments. However, the brain mechanisms that cause these navigational deficits remain a mystery. To shed light on this question at the cellular level, PhD student Johnson Ying from Mark P. Brandon’s Lab at McGill University used thin micron-sized wires to record the brain activity of numerous spatially modulated cell types in a mouse model of AD. In this study, the authors discovered that a specific cell type called “grid cells” in a brain region known as the medial entorhinal cortex were impaired during early pathology.
Johnson Ying won a CAN-CIHR-INMHA Brain Star award for this discovery.
Grid cell activity was simultaneously recorded in animals as they freely navigated a square environment. In healthy mice, grid cells became active in multiple spatial locations which formed a hexagonal pattern that tiled the entirety of space – akin to an internal GPS system. In contrast, the hexagonal pattern in AD mice was broken, suggesting that they could not maintain an accurate internal map of space. Grid cell impairments correlated to deficits in a spatial navigation task. All other spatially modulated cell types in the medial entorhinal cortex were unaffected. These results show that early AD pathology does not disrupt all kinds of spatial coding in the brain, but specifically impairs grid cell spatial firing which may underlie navigational deficits in early AD patients.
These results support the viability of grid cell human fMRI imaging (a brain signal in human beings which is thought to be analogous to grid cells recorded in mice) as an early AD marker that could also be used to assess the efficacy of AD therapeutics administered to patients.
In parallel, these results further justify the use of spatial navigation tests as sensitive behavioral markers of early AD which the clinical field is much in need of.
There is no cure for AD. Multiple AD clinical trials in the past have failed to effectively reverse the damage caused by AD in symptomatic patients. The discovery described here has the potential to help identify AD patients during the early stages of pathology, thus providing clinicians and scientists with opportunities to develop therapies that prevent or delay the appearance of severe disease symptoms such as memory loss.
This work involved recording over 4000 neurons in 68 animals and took 4 years to complete. In all AD mouse model studies to date, this is not only the largest single-unit electrophysiological data set, but the only data set to investigate progressive cellular decline during early pathology. Johnson Ying also collected behavioural data, performed statistical analyses, and wrote the manuscript with his supervisor.
About Johnson Ying
Prior to university, Johnson was highly untalented at rote memorization, multiple choice exams (still is), and performed terribly in his biology courses. The thought of one day studying a biological organ was the furthest thing from his mind. Undecided about his future, Johnson stumbled across neuroscience by complete chance when reading a self-help book that talked about neuroplasticity. The fact that a 3-pound lump of jelly governs one’s thoughts, actions, and emotions fascinated Johnson and he knew that he had found his calling. An impulsive decision to study neuroscience turned into a Ph.D. degree under the mentorship of Dr. Brandon who Johnson crossed paths with during undergrad. Johnson attributes his success to Dr. Brandon for taking a chance on a kid with a lot of heart but no direction, support from lab members, funding from FRQS and CIHR, and his parents who worked tireless as first-generation immigrants. Johnson hopes that his story inspires other young minds who are still undecided about their futures or who may not be the best classroom performers to give research a try. After all, in the laboratory, talent and grades matter to much lesser degrees than passion and an honest work ethic.
Funding sources
This work was funded by CIHR Project Grants #367017 and #377074, an NSERC Discovery Grant #74105, a Scottish Rite Charitable Foundation Grant, a Canada Fund for Innovation Grant, and a Canada Research Chairs award to Mark P. Brandon. Johnson Ying was supported by a Doctoral Training Grant from the Fonds de recherche du Québec, and previously by a Master’s Training Grant from the Fonds de recherche du Québec and a CIHR Master’s Training Fellowship.
Scientific publication:
Ying, J. Keinath, A.T. Lavoie, R. Vigneault, E. Mestikawy, S.E. Brandon, M.P. (2022) Disruption of the grid cell network in a mouse model of early Alzheimer’s disease. Nat. Commun. 13, 886.
