Researchers have identified a new mechanism of neuroplasticity associated with learning and memory

Neurons are important, but they are not the only players in the process. Indeed, it is “cartilage,” clusters of extracellular matrix molecules called chondroitin sulfates located on the outside of nerve cells, that play a key role in the brain’s ability to acquire and store information.

The study, published in the journal Cell Reports describes a new mechanism of brain plasticity, or how neural connections change in response to external stimuli. The paper is titled “Focal Peri-synaptic Matrix Clusters Promote Activity-Dependent Plasticity and Memory in Mice.”

This work is the result of a collaboration between Harvard Medical School, the University of Trento and the German Center for Neurodegenerative Diseases (DZNE) in Magdeburg.

"Sensory skills and the ability to understand our environment depend on the activity of the brain, which allows us to perceive and process stimuli coming from the outside world. Through our brain, we are able to acquire and store new information, as well as remember information that we have already learned, "say Yuri Bozzi and Gabriele Chelini.

"This fascinating phenomenon is made possible by the brain's ability to continuously change the structure and effectiveness of neural connections (synapses) in response to external stimuli. This ability is called synaptic plasticity. Understanding how synaptic changes occur and how they contribute to learning and memory is one of the main tasks of neurobiology."

Yuri Bozzi is a professor at the University of Trento and co-lead author of the article. Gabriele Chelini is the first author of the study. Celini began work on this project in 2017 as a postdoctoral fellow in the laboratory led by Sabina Berretta (McLean Hospital and Harvard Medical School, Boston) and completed the scientific publication while working as a postdoctoral fellow in Bozzi's laboratory at the University of Trento.

The study focuses on chondroitin sulfates, molecules well known for their role in joints, which also play an important function in brain plasticity, being an integral part of the extracellular matrix of the brain, as originally discovered by Dr. Alexander Dityatev's group in 2001.

In 2007, a Japanese study described the presence of round-shaped clusters of chondroitin sulfates scattered seemingly randomly in the brain. This work was forgotten, however, until Sabine Berretta's translational neurobiology laboratory brought these structures back to the scientific community's attention, renaming them CS-6 clusters (for chondroitin sulfate-6, which identifies their precise molecular composition) and demonstrating that that these structures are associated with glial cells and are greatly reduced in the brains of people with psychotic disorders.

Then, in 2017, Gabriele Celini, newly hired in Berretta's laboratory, was tasked with uncovering the function of these clusters.

"We first examined these structures in detail, imaging them at very high resolution. We found that they are essentially clusters of synapses coated in CS-6 and organized into a clearly recognizable geometric shape. We then identified a new type of synaptic organization "say scientists.

"At this point we had to exercise some 'experimental creativity'; through a combination of behavioral, molecular and sophisticated morphological approaches, we realized that these compounds, encapsulated in CS-6 clusters, change in response to electrical activity in the brain."

"Finally, thanks to the collaboration with Alexander Dityatev from DZNE Magdeburg and the efforts of Hadi Mirzapourdelawar from his group, we reduced the expression of CS-6 in the hippocampus (a region of the brain responsible for spatial learning) and demonstrated that the presence of CS-6 is necessary for synaptic plasticity and spatial memory," point out Bozzi and Celini.

"This work paves the way for a new view of brain function. It is possible that all synapses formed on different neurons within CS-6 clusters have the ability to respond together to specific external stimuli and participate in a common function aimed at learning and memory processes " they note.

“They appear to represent a new substrate for integrating information and forming associations at the multicellular level,” add Dityatev and Berretta.

This work is the result of a collaboration between several laboratories, including the Translational Neurobiology Laboratory (Sabina Berretta; McLean Hospital - Harvard Medical School, Boston), the Neurodevelopmental Disorders Research Laboratory (Yuri Bozzi; CIMeC - Interdisciplinary Center for Brain Science, University of Trento) and the molecular neuroplasticity (Alexander Dityatev; DZNE Magdeburg).