Astrocytes emerge as the unexpected conductors of brain networks

A collaborative French–Swiss study reveals a previously unknown role for astrocytes in the brain’s information processing. Published in the journal Cell, the research shows that these glial cells are capable of integrating signals from several neurons at once—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.

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 have 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 the 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 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 different neurons about them. 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 (for comparison, one meter contains one billion nanometers, which corresponds to the size ratio of a hair to the Eiffel Tower) 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 UNIGE 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,” says Karin Pernet-Gallay, research engineer, 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.

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 traveling 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 Volterra.