Through its partnership with Michael Smith Health Research BC, BCSSF is funding research that offers hope to people with schizophrenia. Scientists at UBC’s Anthony Phillips Lab are looking at the role specific receptors play in the brain’s function. When working well, N-methyl-D-aspartate (NMDA) receptors promote connections important to healthy functioning in areas of the brain associated with learning and memory. For this reason, they are often the focus of research into brain-related illnesses. And now Dr. Peter Axerio-Cilies is widening this focus, to include new aspects of these receptors. In so doing, he hopes to understand how certain drugs might work better to improve the performance of these important connections.
Understanding NMDA Receptors
N-methyl-D-aspartate (NMDA) receptors are proteins that play an important role in many brain functions. They contribute to the brain’s neuroplasticity, which is its ability to learn new information. As we age, our receptors lose function naturally. NMDA receptors can also be damaged by injury or disease, which is why they are associated with many illnesses, including Alzheimer’s, Parkinson’s, epilepsy, and schizophrenia. As a result, a great deal of research is dedicated to understanding how exactly these receptors are involved in illnesses and how certain drugs can affect the way they work.
At a cellular level, NMDA receptors work with neurotransmitters and calcium to stimulate neurons, cells which control different functions in our bodies. Neurotransmitters, such as glutamate, dopamine, and serotonin, are the chemicals that send information from one cell to the other. Neurotransmitters do this by travelling across synapses, or connections, between cells.
For information to flow between the cells, first there is an influx of calcium within the sending cell. This opens calcium channels from the sending cell, through which neurotransmitters and calcium flow towards the receiving cell. The neurotransmitters then reach NMDA receptors on the receiving cell, and must bind to these receptors in order to unlock the receiving cells. The NMDA receptors then open up channels into the receiving cell, enabling the movement of neurotransmitters and calcium into the receiving cell.
In the area of the brain associated with learning and memory, the signals contained in these neurotransmitters and calcium can instruct the receiving cells to grow the synapse, or create new ones, helping your brain to learn new information and form memories.
Dr. Peter Axerio-Cilies is contributing to this important body of research by exploring how certain drugs might improve the performance of NMDA receptors. We asked him to explain his research and how it represents a new hope for patients with schizophrenia.
Why are researchers interested in studying NMDA receptors?
It’s such an important protein for memory as well as behaviour. It is super sensitive, so if you literally touch the protein in any way possible, you get some kind of big response. Whereas, if you use any other protein, you might not see any change. So, our research is asking, “How can we make it back to normal? How do we make it so that if there is this dysfunction, we could theoretically get it back to normal levels?”
What is the significance of NMDA receptors in patients with schizophrenia?
The whole gateway of how one cell communicates with another is through NMDA receptors. It is the protein that sits at the surface of the synapse that makes the synapse grow and lets memory be formed. If you block NMDA then you will have lack of memory. It’s literally a door or channel that opens and closes. In the microscope it looks like a tunnel. Calcium goes through the tunnel and serves as the chemical that communicates. Neurotransmitters like glutamate stick to the NMDA receptors and open the tunnel allowing calcium to go through into the receiving cell and tell it to make other synapses. The more synapses you have, the stronger the cell is, the better memory you have and the easier it is to recall that memory. It’s a bit like eating spinach. If it’s too little, the synapses don’t grow and may even shrink. In schizophrenia, you have less calcium going through, which means the synapses don’t grow. They all shrink. That’s when you lose memory.
Why did you choose to focus your research on schizophrenia?
I wanted to choose something that people are interested in, something useful. I did my Bachelor’s in Chemistry and then a Master’s in Pharmaceutical Science. From there, I spent time in prostate cancer research, looking at how drugs react in the body. I was encouraged to do a PhD and invited to become part of a project that would be developing drugs that would help more than one disease, including Alzheimer’s, schizophrenia, depression, and even stroke patients. What they all have in common is a link to the NMDA protein in the brain. I said, “Why don’t I do my postdoc with these drugs? What can I do to optimize them, get them ready, characterize them – everything I need to show people that it works in patients with schizophrenia?” I knew I wanted to prove that they’re good for this type of disease.
Describe your study.
There are four types of NMDA – A, B, C and D. They’ve found after years of study that they are all located in different areas of the brain. A (or GluN2A) and B (or GluN2B) are in the synapse, which means they are both gateways between two cells. C (GluN2C) and D (GluN2D) are mostly relevant to a different part of the brain. I am looking at A and B. People have tried to design drugs for these, but the main problem is that everyone was targeting just A. I am trying to find a drug that could increase both A and B, because we know B is important for memory as well. We have learned that hitting just A isn’t effective, so I am looking to see if targeting both is more effective. So far, I’ve found that I’ve increased function more than 600%.
How will your research improve the lives of those suffering from schizophrenia?
In schizophrenia and Alzheimer’s patients there are fewer synapses. When this protein is taken away in rodents, they exhibit the symptoms of schizophrenia. If you affect the NMDA, you affect dopamine (another area of study). They are all interconnected. The NMDA sticks to dopamine, and the systems work in tandem. If you mess up one, you mess up the other. If we can find the mechanism – a drug – that would stick to another place on the protein and allow it to influx more calcium, that would allow things to stay where they are or make it stronger.
We are making the NMDA do more than it is supposed to. The drug I designed will stick to the NMDA and allow it to open more. By increasing its performance, you’re boosting the cell’s ability to grow and function in a more superior state. The drug is not addictive (because it does not work on the reward system – dopamine) and can be stopped at any time. If patients have dysfunctional NMDA, the drug will alleviate the symptoms, IQ will be better, and hallucinations will stop.
What stage is your study at now?
The research is at the stage where we are testing the drug’s effects on animals. As with any drug that affects brain function, proper clinical trials are needed before it can be tested on humans. There are other drugs that have been evaluated already that have the same mechanism, which would shorten the timeline. We hope to secure funding to push these drugs forward. It’s good to have that groundwork, but we also want to find the best strategy that can be used to expedite the process. The bottom line is that science is expensive, and we are always looking to secure more funding.
BCSSF funding in partnership with Michael Smith Health Research BC secured Dr. Axerio-Cilies’ salary at UBC’s Anthony Phillips lab for 3 years and the drug evaluation stage of the research. The team is in the process of securing funding for drug development and pre-clinical development.