Professor Richard Morris CBE FRS, is a Professor of Neuroscience and Director of the Centre for Cognitive and Neural Systems at the University of Edinburgh. His research focus is on the neurobiology of learning and memory. It is for work in this area that he was awarded the 2016 Brain Prize along with Professor Tim Bliss and Professor Graham Collingridge.
What is LTP and why is it important?
LTP is a long lasting phenomenon involving connections from one set of cells to another set of cells. It’s widely known that the brain consists of millions of cells which are connected together, and one might imagine that a great deal of the connectivity of the brain is laid down genetically. That is certainly true, but on the other hand there is all sorts of fine tuning of these connections, and on top of that the discovery of LTP revealed that it was possible, with a particular pattern of activity in the brain, to change the strength of those connections.
Your research has its basis in how learning and memory happen in our brains – what can LTP teach us about this?
When the original paper was published, by Tim Bliss and Terje Lømo in 1973, they speculated that this potentiation may be the basis of learning and memory – but they were working with anaesthetised animals and didn’t do any memory experiments. The second step of the story was provided by Graham Collingridge and his colleagues in Bristol, who were working on communication between brain cells and the development of drugs that would affect different aspects of that communication. They developed a drug that has come to be known as AP5. What AP5 does is act very selectively at a particular receptor, called the NMDA receptor, which is responsive to the chemical messenger glutamate and it appears that when you activate this receptor, you create the opportunity for change in the strength of connections. So my group came along last, as it were, and we were doing behavioural experiments in animals, and we were the first people to ask whether AP5 would actually have functional effects in behavioural experiments. We discovered that when given AP5, animals have great difficulty in spatial learning, but interestingly if you had taught the animals a solution (to their experimental task) beforehand, they would have no problem with retrieval. So, communication would be normal, but the ability to change the communication was altered – that was the way in which we went from an original observation of LTP, through pharmacological alteration, to behaviour.
LTP is a very important facet of modern day teaching and research – where is the field going now?
At the functional level, research is looking at whether LTP is just in the hippocampus, the centre of learning and memory, or does it occur at other connections, for example in the neocortex. It now looks as though LTP is more generic and so if you look at, for example, the amygdala, and block certain connections there with AP5, you can block emotional rather than spatial learning and similarly there are effects in the neocortex.
There have been studies showing alterations of the receptors in schizophrenia and there’s also work related to depression, but that may be secondary to aspects of depression that are currently known. If we look at the other end of the spectrum, there’s the whole question of what are the specific genes that make up NMDA receptors. There’s some very exciting work going on at the molecular end, asking questions about the chemical pathways inside brain cells that NMDA receptors connect into. And then inbetween the two, there’s a great deal of research, trying to ask the question of how do all these different types of physiological phenomena fit together in the normal functioning of the brain.
Do you see your research into LTP as having an important outcome in fighting classic diseases of memory such as Alzheimer’s disease (AD)?
I think it does, but I think it’s quite important to make a distinction between these discoveries and the idea that they might have an impact on the prevention of something like AD. There are disease mechanisms that may have nothing to do with LTP, or the NMDA receptor, and we don’t want to claim that these discoveries will be any kind of cure or prevention to this terrible disease.
However, it’s now becoming more apparent that long before disease pathology is seen in the brain there are changes happening at these points of connections. Now, as we have said, these connections are critical for proper memory function. This would suggest that early stage AD has altered memory function – and that is exactly right. There is a large effort that is being made to identify drugs that act on the NMDA receptors or act on pathways downstream of it – an interesting avenue for creating drugs that may help combat the memory losses seen in AD.
The prize has brought LTP into the spotlight – what is the key message about the brain that LTP can show us?
I think a key idea is that the brain can change, and for people facing difficulties, like recovering from stroke or overcoming learning disabilities, what this discovery means is that we can offer an optimistic attitude to interventions that make use of the brain’s own mechanisms of plasticity.
Image: The Brain Prize