“It’s fascinating how such a small molecule can influence changes in our behaviour”

Last month, Harold MacGillavry was awarded the ERC Starting Grant. With the 1.5 million Euros provided by the prestigious grant from the European Union, he will study the movement of molecules at the junction between nerve cells. That movement is important for the transmission of stimuli, and defects in the movement may play a role in autism or dementia.

Textbooks always show them drawn neatly in a row: the receptors that facilitate contact between two nerve cells. But it is now clear that these receptors are constantly in movement, and that they occasionally clump together at specific locations within the synapse, or the point of contact between the neurons. Neurobiologist MacGillavry would therefore like to study why they do so, and how the process is regulated.

One molecule at a time

Since super-resolution fluorescence microscopy became available a few years ago, scientists have been able to study the structure and dynamics within the synapse using the ‘single molecule imaging’ technique. This involves researchers marking the receptors with a fluorescent substance and examining them each individually. The computer then reconstructs a more detailed image.

“With the old technique, the images were too vague to really look into the synapse”, MacGillavry explains. “Now we can zoom in further and study cellular structures that are up to 10 times smaller.” “And the technique allows us to follow the movement of a single molecule in a living cell in real time!” He adds, enthusiastically.

Glutamate

MacGillavry became acquainted with the technique while working as a postdoc in Baltimore after earning his PhD at the VU Amsterdam. There he proved that the receptors for the neurotransmitter glutamate are not evenly distributed across the synapse, but rather bunch together in clumps known as ‘nanodomains’. When he then received a VENI grant from NWO, he moved his work to Utrecht University’s Cell Biology department.

“There are several types of glutamate receptors”, he explains. “They all move freely across the cell membrane, but sometimes they stay in one place for a time. One type does that in the middle of the synapse, while another tends to stop more on the side.” MacGillavry wants to study how they end up in such specific locations: For example, I want to know if they interact with other proteins, and what role the synapse membrane plays.”  To do so, he removes certain proteins from the synapses of cultured rat neurons, and then examines the effect this has on the movement of receptors.

Stronger signal?

Above all, MacGillavry wants to know how the receptor clumps determine the function of the synapse; how they influence the transmission of signals. To study that, he must make visible the nerve cell’s electric potential. “The fun thing is that we will also directly manipulate the domain organisation. That means moving the receptors that are normally located on the side, where they interact with less glutamate, to the middle where they suddenly come into contact with an overabundance of glutamate. What happens then? Does the signal become larger, or last longer? That’s what we’re going to test.”

Autism

Glutamate is a common neurotransmitter involved in a wide range of brain functions. That makes it an important target for studies into brain diseases and psychiatric disorders such as autism, Alzheimer’s, schizophrenia and addiction. “We know that the glutamate receptors with a preference for the side of the synapse are different in autism. That has been proven with genetic research using animal models,” says MacGillavry.

But continuing that line to the patient is a major step. “Once we understand the dynamics of the receptors, that can help pharmaceutical companies to develop new medications. I hope that my research will eventually result in better treatments. It’s fascinating to me how such tiny molecular changes can influence things like memory and behaviour.”