Neuroscientists from the University of Lausanne (UNIL) and the Wyss Center for Bio and Neuroengineering in Geneva have used a range of molecular, imaging and genetic tools to identify a new type of cell in the brain that sits somewhere between neurons and glial cells. Discovery of this atypical subpopulation of specialized cells—which the team refers to as glutamatergic astrocytes—offers scientists new insights into the complex roles of astrocytes in central nervous system (CNS) physiology and disease, highlighting a potential therapeutic target.

“In between neurons and astrocytes, we now have a new kind of cell at hand,” said Andrea Volterra, PhD, honorary professor at UNIL and visiting faculty at the Wyss Center, co-director of the study. “Its discovery opens up immense research prospects. Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here.”

Volterra is senior and co-corresponding author of the team’s published paper in Nature, titled “Specialized astrocytes mediate glutamatergic gliotransmission in the CNS,” in which the researchers noted, “… our study adds to the understanding of astrocyte diversity, suggesting that different groups of specialized astrocytes have distinct roles in brain function … By uncovering this atypical subpopulation of specialized astrocytes in the adult brain, we provide insights into the complex roles of astrocytes in central nervous system (CNS) physiology and diseases, and identify a potential therapeutic target.”

It has long been recognized that brain function depends on the ability of neurons to rapidly elaborate and transmit information through their networks. To support them in this task, glial cells perform a series of structural, energetic and immune functions, as well as stabilize physiological constants. Astrocytes are a type of glial cell that intimately surround synapses, the points of contact where neurotransmitters are released to transmit information between neurons.

Neuroscientists have long suggested that astrocytes may have an active role in synaptic transmission and participate in information processing. However, studies conducted to date to demonstrate this have reported conflicting results and there is yet no definitive scientific consensus. By identifying a new cell type with the characteristics of an astrocyte and expressing the molecular machinery necessary for synaptic transmission, Volterra and colleagues may have put an end to years of controversy.

To confirm or refute the hypothesis that astrocytes, like neurons, are able to release neurotransmitters, researchers first scrutinized the molecular content of astrocytes using modern molecular biology approaches. Their goal was to find traces of the machinery necessary for the rapid secretion of glutamate, the main neurotransmitter used by neurons.

“The precision allowed by single-cell transcriptomics approaches enabled us to demonstrate the presence in cells with astrocytic profile of transcripts of the vesicular proteins, VGLUT, in charge of filling neuronal vesicles specific for glutamate release,” explained study codirector Ludovic Telley,  PhD, an assistant professor at UNIL. “These transcripts were found in cells from mice, and are apparently preserved in human cells. We also identified other specialized proteins in these cells, which are essential for the function of glutamatergic vesicles and their capacity to communicate rapidly with other cells.”

 Next, neuroscientists tried to find out if these hybrid cells were functional, that is, able to actually release glutamate with a speed comparable to that of synaptic transmission. To do this, the research team used an advanced imaging technique that could visualize glutamate released by vesicles in brain tissues and in living mice. “We describe a subpopulation of specialized astrocytes with a discrete molecular signature resembling that of glutamatergic synapses, defined anatomical distribution and functional competence for VGLUT-dependent glutamate release in situ and in vivo,” the authors wrote. Volterra added, “We have identified a subgroup of astrocytes responding to selective stimulations with rapid glutamate release, which occurred in spatially delimited areas of these cells reminiscent of synapses.”

In addition, the glutamate release exerts an influence on synaptic transmission and regulates neuronal circuits. The research team was able to demonstrate this by suppressing the expression of VGLUT by the hybrid cells. “They are cells that modulate neuronal activity, they control the level of communication and excitation of the neurons,” added Roberta de Ceglia, PhD, first author of the study and senior researcher at UNIL. And without this functional machinery, the study shows that long-term potentiation, a neural process involved in the mechanisms of memorization, is impaired and that the memory of mice is impacted. “The contextual memory defect observed after astrocyte VGLUT1 deletion indicates that glutamatergic astrocytes have a function in physiological memory processing,” the team noted.

The implications of this discovery extend to brain disorders. By specifically disrupting glutamatergic astrocytes, the research team demonstrated effects on memory consolidation, but also observed links with pathologies such as epilepsy, in which seizures in mice were exacerbated. The observed protective function of astrocyte VGLUT1-dependent signalling against induced seizures in mice, is worth examining further in chronic epilepsy models for possible therapeutic perspectives, the investigators further noted. Finally, the study showed that glutamatergic astrocytes also have a role in the regulation of brain circuits involved in movement control, and so could potentially offer therapeutic targets for Parkinson’s disease. The findings, they noted, “… testify to the functional relevance of these specialized astrocytes, despite their relative numerical paucity, and highlight their potential as targets for CNS protective therapies.”

In their conclusion, the scientists stated, “Future studies are expected to generate CNS-wide maps that will help to define the overall distribution of glutamatergic astrocytes and their full range of actions, and to better understand why this atypical astrocytic population exists and by which specific modalities it integrates anatomically and functionally into CNS circuits, as well as if and how its altered properties contribute to defined pathological CNS conditions.”

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