Earlier this year, Graham Collingridge, chair of U of T’s physiology department, shared the “Nobel of neuroscience” – the $1.5-million Brain Prize – with two other scientists. They received the award for their work on “long-term potentiation,” a model for understanding how memories form. Scott Anderson spoke with Collingridge about his research and how it could lead to better treatments for Alzheimer’s disease.
What is long-term potentiation and why is it important?
The great Canadian psychologist Donald Hebb put forward the idea that when two neurons are active at the same time, the connections between them get stronger (“neurons that fire together wire together”). Tim Bliss, one of the co-winners of the Brain Prize, discovered long-term potentiation (LTP), a process by which a brief period of intense neuronal activity leads to a long-lasting increase in the connections between the nerve cells. This is now regarded as the most important model for understanding learning and memory in mammalian brains.
What was your contribution?
I was a post-doc working on glutamate, one of the major neurotransmitters in the brain. When glutamate is released from a nerve cell it binds to a protein called a receptor. One of these receptors is called N-methyl-D-aspartate (NMDA). After a series of experiments, I proposed that the NMDA receptor triggers the first part of the long-term potentiation process. A few years later, Richard Morris (the third co-winner of the Brain Prize) showed in experiments with rodents that blocking this receptor does indeed impede learning.
Does this explain why some memories stay with us and others don’t?
To an extent, yes. Long-term potentiation is very sensitive to modulation. This is important because we’re constantly being bombarded by information and we have to sift out what’s trivial and can be forgotten and what we need to remember. This decision is most probably made by neuromodulators, such as noradrenalin, which is released along with adrenalin when the body is very active. It signals to the memory mechanism that this is important information and that we need to learn and remember this.
So when we’re very excited or fearful, for example?
Yes, one function of the adrenalin released into the brain is to say that this is a stressful or dangerous situation that you don’t want to do again. So memory is enhanced.
What do we know about long-term potentiation now that we didn’t know when you started?
Since I observed the role of the NMDA receptor, hundreds of labs around the world have worked on this process. We know the NMDA receptor is just the initial trigger. We also know that the receptor that is actively involved in storing memories is called the AMPA receptor. Between the activation of the NMDA receptor and the AMPA receptor, there’s a “molecular machine” that involves hundreds of proteins. We know the identity of some but not all of them. And we certainly don’t fully understand the sequence of events.
What important questions are you working on now?
I’m interested in translating my research to create better treatments. There’s increasing evidence that errors in the long-term potentiation process are causally related to conditions such as autism and schizophrenia. It seems very likely that dysregulation of LTP is involved in stress, addiction, anxiety and depression. We are also very interested in Alzheimer’s disease, since typically the first thing that goes wrong in this dreadful disease is the ability to learn new information.
What are you investigating specifically related to Alzheimer’s disease?
Long-term potentiation is an increase in the strength of synaptic connections. But the brain has a way of decreasing the strength of synaptic connections too; it’s called “long-term depression” or LTD. This is important because you need a balance between potentiation and depression of synapses. You can’t go through life making all your synapses stronger. We believe Alzheimer’s disease is caused by a shift in the normal balance between LTD and LTP, such that you get a reduction in LTP and correspondingly too much LTD.
How could your research lead to new or better Alzheimer’s medications?
If we better understood the “molecular machine” involved in learning and memory, it would be easier to design more effective Alzheimer’s drug. But we don’t have the time to wait until we know the complete system. If we can establish that a certain component is involved, then we can test the therapeutic potential of modulating its actions The challenge is that most of the LTP and LTD molecules are involved in other processes in the body as well. For example, the protein GSK3-beta is known to be involved in Alzheimer’s disease. Drug companies have developed GSK3-beta antagonists. In principle they will delay neurodegeneration, and there’s good preclinical evidence that this is the case. But the problem is that GSK3-beta is expressed in every cell in the body and if you inhibit it, the side-effects include cancer. We aim to find molecules that are important only to long-term depression since these could be the best therapeutic targets.
What has winning the Brain Prize meant to you personally and for your research?
Personally, it’s great to get the recognition that what you’ve been working on means something to people. But what’s more important is that it raises the profile of neuroscience.
What would you be doing if you weren’t a brain scientist?
I’d like to have been a professional soccer player, but I never had the talent.
Why did you come to Toronto?
U of T is one of the world’s leading universities and undoubtedly number one in Canada. It’s also connected to several fantastic hospitals with their own research institutes. You don’t see that integration in many places. My research is at the point where I really want to try to translate my ideas into new treatments for brain disorders. So being in an environment where lots of people are medically qualified to help me do this makes it a very good place to work.
A shorter version of this Q&A was published in the Autumn 2016 print edition.
Fighting for Justice
In her latest documentary, filmmaker Nisha Pahuja tackles a most difficult topic – sexual assault
Rogers Foundation Gives $90 Million to Usher in New Era in Cardiac Care
Gift will enable the Ted Rogers Centre for Heart Research to expand its research into heart failure – and save lives
Solving a Climate Puzzle, One Tree Ring at a Time
A natural archive reveals how Canada’s arctic climate has changed over the past 1,000 years