Meet the GRI Researchers: Dr. Graham Collingridge
Dr. Graham Collingridge, a member of the scientific advisory board at CureGRIN, is the Director of the Tanz Centre for Research in Neurodegenerative Diseases (CRND) at the University of Toronto and a Senior Investigator at the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
Dr. Collingridge is interested in understanding the mechanisms that underlie synaptic plasticity. This means that he studies how the synapses, which are the points of communication between neurons, change their strength and therefore allow processes like learning and memory. To study this process, Dr. Collingridge focuses on the function of NMDA receptors. Broadly, Dr. Collingridge is interested in how variations to processes controlled by NMDA receptors contribute to disorders like Autism, Neurodegenerative Disorders, Depression, and Chronic Pain.
Dr. Collingridge and his lab will contribute to answering two main questions about GRIN Disorder. First, their research will provide a better understanding of how NMDA receptors function normally to allow the storage of information, like memories. Although the scientific community has made a lot of progress in this area, there are still many unknowns. Therefore, continuing to study these receptors will provide additional insights that may guide therapeutic development. The second question that their research seeks to answer is what is causing the dysfunctional NMDA receptor in specific variants of children with GRIN Disorder. By studying one specific variant in-depth, Dr. Collingridge hopes to reveal the underlying molecular change that leads to disorders. Understanding normal receptor functioning as well as how variants produce changes that differ from this normal functioning will help optimize both short-term and long-term treatments.
To answer the question of how variants lead to abnormal NMDA receptor functioning and therefore symptoms of GRIN Disorder, the Collingridge lab is currently studying one specific variant of GRIN1. So far, Dr. Collingridge has discovered that the variant is a loss of function variant that causes a reduction in NMDA receptor functioning of 50% in the hippocampus. This finding is significant because it shows reduced NMDA receptor functioning in a brain area that is very important for learning and memory. The lab’s current hypothesis for why this reduction in NMDA receptor functioning occurs is that only half of the normal receptor is made, but this has not yet been established. Therefore, in the next year, the lab will continue to conduct more experiments to see if this hypothesis is supported.
Another priority of Dr. Collingridge’s research in the next year is to look at the possibility of using modulators to rescue the deficits produced by the variant. So far, memantine, which is used clinically, and D-cycloserine, which enhances the activity of NMDA receptors, have produced negative results in preliminary experiments. However, the effect of other positive allosteric modulators (PAMs), which help the functioning of proteins like NMDA receptors, will be studied. Since the variant that they are studying reduces the functioning of NMDA receptors by half, Dr. Collingridge is excited to see if PAMs can be used to restore this reduced functioning. In a recent paper published in Neuropharmacology, Dr. Collingridge and his lab investigated whether PAMs that target different areas of the NMDA receptor would have different effects on the various types of synaptic plasticity. To test this question, experiments were performed using slices of rodent brain. They first determined that different PAMs do indeed have different effects on different types of plasticity (changes in the brain). For example, one PAM enhanced long term potentiation, which allows learning and memory, while another PAM decreased long term potentiation.
If functioning can be improved with molecules like PAMs, the next step would be to see if the behavioural deficits can be reversed. Seeing that studying the behaviour in mice is an important outcome, their lab is also interested in expanding how the characteristics of mouse models of GRIN Disorder are defined.
The last future direction for Dr. Collingridge’s lab is an exciting collaboration with other researchers including Dr. Amy Ramsey, another member of the scientific advisory board at CureGRIN. The goal of this collaboration is to determine if it is possible to genetically rescue this variant, either by providing greater amounts of the normal functional gene or by replacing the variant with the normal gene. These techniques are still not possible in humans, but the results may help guide therapies that could benefit people with GRIN Disorder in the future.
Written by: Melissa Finlay (CureGRIN Scientific Volunteer, University of Toronto student)
Edited by: Meagan Collins (CureGRIN Research Coordinator)
To learn more: France G, Volianskis R, Ingram R, Bannister N, Rothärmel R, Irvine MW, Fang G, Burnell ES, Sapkota K, Costa BM, Chopra DA, Dravid SM, Michael-Titus AT, Monaghan DT, Georgiou J, Bortolotto ZA, Jane DE, Collingridge GL, Volianskis A. Differential regulation of STP, LTP and LTD by structurally diverse NMDA receptor subunit-specific positive allosteric modulators. Neuropharmacology. 2022 Jan 1;202:108840. doi: 10.1016/j.neuropharm.2021.108840. Epub 2021 Oct 20. PMID: 34678377; PMCID: PMC8803579. https://pubmed.ncbi.nlm.nih.gov/34678377/
