Astrocytes, the unexpected conductors of brain networks

 

Dozens of synapses from distinct neural circuits gather around a specialised astrocyte structure called a leaflet, which is capable of detecting and integrating the activities of multiple synapses.
Image Credit: © Lucas BENOIT et Rémi GRECO/ GIN

A collaborative study between the Universities of Lausanne (UNIL) and Geneva (UNIGE), the Grenoble Institute of Neuroscience (GIN) and the Wyss Centre for Bio and Neuroengineering reveals a previously unknown role for astrocytes in the brain's processing of information. Published in the journal Cell, their study shows that these glial cells are capable of integrating and processing signals from several neurons at once. Using cutting-edge imaging techniques, the team identified new specialised structures called leaflets, which enable astrocytes to connect several neurons, and thus neural networks. This represents a conceptual shift in our understanding of the brain.

The brain does not function via neurons alone. In fact, nearly half of the cells that make up the brain are glial cells, and among them, astrocytes occupy a special place. Their name comes from their star-shaped skeleton, but their external appearance is more reminiscent of certain nebular stars, with an irregular, filamentary contour that allows them to insert themselves into the smallest gaps between neurons, blood vessels, and other cells. They are thus in close contact with synapses, the communication hubs between neurons.

"We have demonstrated for the first time that astrocytes are not limited to responding to a single synapse."

Since the 1990s, neuroscientists have therefore suspected that astrocytes actively participate in the transmission of information by using calcium as a messenger molecule. This small chemical component can trigger a cascade of reactions in the cell, including the release of molecular transmitters that can modulate synaptic activity. For these signals to occur, an internal structure called the endoplasmic reticulum (ER) is essential: it stores calcium and releases it under certain conditions. Despite numerous hypotheses, the exact roles of these calcium signals remained unclear, particularly in the minutest areas of astrocytes in direct contact with synapses, because they are particularly difficult to observe due to their tiny size. A research team bringing together universities  of Lausanne (Unil) and Geneva (UNIGE), Inserm and Grenoble Alpes University (Grenoble Institute of Neuroscience, GIN), and the Wyss Center for Bio and Neuroengineering has just filled this gap.

Beyond the simple synapse

Until now, astrocytes were perceived as acting on the margins of neuronal synapses. The so-called “tripartite synapse model” attributed an auxiliary role to them: modulating activity between two neurons. But the current study reveals a much more central role: astrocytes do not simply interact with a single synapse - they simultaneously coordinate several synaptic inputs from different neurons achieving a new level of spatial and temporal integration of the information.

The study, published in Cell on September 24, reveals that specific extensions of the astrocyte membrane, dubbed leaflets, envelop the synapses, contain ERs, and are interconnected through tunnels called gap junctions to form a single functional domain. In each of these domains, a small amount of calcium is released each time a neighboring synapse is active. Thus, one single leaflet can integrate the signals from about then, or even more, different neurons. The domains then release larger amounts of calcium, mirroring the integration of the various neuronal signals received. This calcium in turn promotes the release of factors that can regulate communication between the synapses enclosed within the leaflet.

Far from being simple relays, the scientists thus consider astrocytes as active computational elements of the brain. “We have demonstrated for the first time that astrocytes are not limited to responding to a single synapse, but can integrate signals from entire neural circuits. This opens the door to new cognitive functions carried out by these glial cells,” explains Andrea Volterra of Unil’s Department of Fundamental Neuroscience, honorary professor at the Faculty of Biology and Medicine and study co-director.

Exploring every corner of the brain

To observe these unprecedented interactions, the team combined two cutting-edge techniques: nanoscopic resolution volumetric electron microscopy and an optical microscopy technique. “We developed it specifically for this study so that we could visualize calcium changes in very small volumes,” says Nicolas Liaudet, an engineer at the Bioimaging Platform of the UNIGE Faculty of Medicine and co-author of the study. This approach made it possible to visualize the leaflets in their exact environment and to evaluate simultaneously their composition, connectivity, and dynamic role. “Our methodological synergy was key to achieve this new level of understanding,” indicates Karin Pernet-Gallay, director of the Electron Microscopy Platform at the Grenoble Institute of Neurosciences and co-director of the study. 

The leaflets, less than 250 nanometers in size, originate from the cell body of the astrocyte or from its main extensions, do not contain mitochondria, but possess fragments of the endoplasmic reticulum (ER) and the molecular machinery capable of generating calcium signals. They are close enough to synapses to respond to their signals and interconnected among each other to coordinate broader responses. By genetically removing part of the molecular machinery that enables calcium signaling in astrocytes, the researchers were able to demonstrate that tiny calcium signals originate in the leaflets themselves as a result of synaptic activity. Andrea Volterra explains that the leaflets are, in a way, “biochemical control towers, independent from the rest of the astrocytes. They seem to be there to survey and coordinate the information travelling in each synaptic trajectory according to a higher-level plan.”

Cognitive and clinical functions to be explored

The study’s results show that astrocyte activity is correlated with neuronal signals in the synapses, but also that it is amplified when several neurons are active at the same time. This capacity for integration potentially makes astrocytes large-scale controllers of brain activity, rather than simple local regulators at the level of an individual synapse.

These discoveries offer new avenues for understanding higher brain functions such as memory, emotions, consciousness and decision making. They could also explain certain dysfunctions observed in brain pathologies. “It is likely that astrocytes play a protective or aggravating role depending on the pathological context. We will now study their involvement in memory and neurocognitive degeneration such as Alzheimer’s disease,” concludes Andrea Volterra.

Published in journal: Cell

Title: Astrocytes functionally integrate multiple synapses via specialized leaflet domains

Authors: Lucas Benoit, Ines Hristovska, Nicolas Liaudet, Pierre-Henri Jouneau, Arnold Fertin, Roberta de Ceglia, David Litvin, Maria Amalia Di Castro, Milica Jevtic, Ioannis Zalachoras, Toko Kikuchi, Ludovic Telley, Matteo Bergami, Yves Usson, Chihiro Hisatsune, Katsuhiko Mikoshiba, Karin Pernet-Gallay, and Andrea Volterra

Source/Credit: Université de Genève

Reference Number: ns092425_01

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