Restless Receptors

Today, it is known that receptors move very rapidly and that this mobility plays an essential role in the signal transmission between neurons. In fact the mobility of receptors controls the reliability of neuronal transmission. “We have revealed that a minor modification of the mobility has a major impact on high frequency transmission. In addition this mobility enables the replacement of desensitized receptors by naïve receptors within a few milliseconds,” Choquet states. This reduces synaptic depression and allows the neuron to transmit information at a higher frequency. These results have radically changed the understanding of neuronal physiology. “Besides the electrophysiological techniques, the light microscopic techniques have played a decisive role,” Choquet explains. “They have literally shed new light on signal transmission functionality and synaptic plasticity.”

Currently, the team of Choquet is consolidating this knowledge by pursuing two different lines of research. “We are extending our experiments, which have concentrated up to now on cell cultures and brain sections, to include ex vivo investigations and even studies of living organisms”, explains Choquet. “Only then can we gain a better understanding of how learning and memory are actually influenced by the regulation of receptor movements. On the other hand, we intend to research receptor mobility within the synapse on a nanometer scale down to the smallest detail in order to find out, for example, how scaffold proteins are involved in the regulation of receptor mobility. Our working hypothesis is: different information speeds and regulations are directly related to learning and memory.”

The group’s work has quite a relevance for the research of neuronal diseases. “Today, we assume that changes or malfunctions at synapses play a definite role in neuronal and psychological disorders. That’s why not only neurodegenerative diseases, but also epilepsy or autism are also called synaptopathies. Of course, our basic molecular research of the animal model is still far from being clinically relevant, but our work is already linked to that of the colleagues in pathology.” For instance, they have begun, using animal models, to examine the defects in receptor trafficking that are observed in Alzheimer’s and Parkinson’s disease. A whole department of the INB is occupied with neurodegenerative diseases.

Choquet considers heading the BIC an added advantage for his research. “In Bordeaux, I had the dual function as head of a research group and Head of the Imaging Facility right from the beginning. I have taken care to make the imaging tools we develop for our own experiments available to the entire community", he says. "Since then, the facility has steadily grown – like my research group. In its present size and function as core facility, the BIC has evolved from the fusion of the light microscopy (LM), electron microscopy (EM) and the plant imaging facility."

 The team is very successful with the further development of imaging technologies. In 2002, they managed to obtain the first live images of the movements of AMPA receptors (AMPAR), a sub-group of the glutamate receptors, in the cell membrane by using a relatively crude approach of tracking by video microscopy of micrometer-sized latex beads bound via antibodies to AMPAR subunits. However, this method is not suitable for tracking receptors inside the synapse. Together with the physics group of Bordeaux 1, they then started developing single molecule detection techniques.

They were the first group in Europe to apply this technique successfully to living neurons. Another method they developed is the  photothermal imaging of nanogold particles to track receptors in live neurons for long periods. "Although the gold particles do not bleach or blink, and allowing theoretically infinite recording times, spontaneous photothermal signals from mitochondria may interfere with the tracking of gold particles", the scientist says.