The individuality of synapses
The human brain is comprised of about 85 billion neurons. Using a combination of electrical and chemical signals, these neurons communicate with each other, enabling us to move, think and feel. The meeting point where this communication happens is called a synapse. Yet while every synapse transmits signals, not all synapses do so equally. This has long been a mystery. But research by the EU-funded Dyn-Syn-Mem project has shed new light on the inner workings of the nervous system. “We wanted to understand how the nano-organisation and mobility of neurotransmitter receptors at synapses determine the functional specialisation of neuronal connections,” says Daniel Choquet(opens in new window), a researcher at the French National Centre for Scientific Research(opens in new window) (CNRS) and University of Bordeaux(opens in new window), the project’s coordinating partner. The project received support from the European Research Council(opens in new window).
New insights into information processing, learning and memory
With a focus on AMPA-type glutamate receptors (AMPARs), the main mediators of fast excitatory transmissions, the project developed and applied cutting-edge, super-resolution imaging, single-particle tracking and molecular engineering to visualise, manipulate and analyse receptor dynamics within intact brain tissue. “By integrating these tools with physiological and behavioural assays, we were able to explore how nanoscale receptor organisation contributes to information processing, learning and memory,” explains Choquet.
Implications for understanding cognitive decline
The project’s multidisciplinary approach led to several transformative findings. For example, as to memory, researchers identified early nanoscale defects in AMPAR dynamics that precede neuronal loss and cognitive decline, making them promising biomarkers or therapeutic targets. The project also found that AMPARs are organised into dynamic nanoclusters, called nanodomains, and that these nanodomains govern synaptic strength and plasticity by tuning local receptor concentration. “We discovered that the properties of these nanodomains differ across synapses, conferring a molecular signature that determines each synapse’s functional identity,” adds Choquet. Beyond these scientific findings, the project developed innovative molecular tools and quantitative imaging pipelines that are now being used by researchers worldwide to explore receptor function in health and disease.
Redefining the concept of synaptic diversity
Dyn-Syn-Mem has redefined the concept of synaptic diversity. “Instead of seeing synapses as uniform entities, we now know that the nanoscale distribution and mobility of receptors shape how individual synapses compute and respond to activity,” notes Choquet. According to Choquet, this discovery is critical to understanding how the brain encodes and stores information. “Thanks to our work, alternations in receptor nano-organisation are now recognised as early contributors to cognitive dysfunction in disorders like Alzheimer’s, Huntington’s disease and autism spectrum disorders,” he says. The project’s work also supports key EU priorities in neuroscience and healthy ageing, offering new conceptual and technological foundations for treating brain diseases.
From receptor dynamics to brain disorders
To continue down the path of treating brain diseases, researchers are investigating how pathological brain states – such as chronic stress, neuroinflammation, ageing or genetic mutations – alter the nanoscale organisation of synapses. They are also testing whether restoring physiological receptor dynamics through targeted interventions can rescue cognitive function in disease models. “The next frontier is translational and will see us applying what we have learned about receptor dynamics to brain disorders,” concludes Choquet.