Summary: Neuroscientists have unveiled a new hybrid cell, straddling the line between the well-known neurons and glial cells in the brain.
Previously, glial cells, especially astrocytes, were believed to merely support neuron functions. However, recent research highlights the ability of these cells to release neurotransmitters and directly influence neural circuits.
This groundbreaking discovery challenges traditional beliefs about brain cell functionality and paves the way for novel therapeutic strategies.
A new hybrid cell type, located between neurons and astrocytes, has been identified that can release neurotransmitters.
Modern molecular biology techniques confirmed that astrocytes possess machinery necessary for the rapid secretion of glutamate.
Disruption of these hybrid cells’ functionality impacts memory, has links with epilepsy, and offers therapeutic insights for Parkinson’s disease.
Source: University of Lausanne
Neuroscience is in great upheaval.
The two major families of cells that make up the brain, neurons and glial cells, secretly hid a hybrid cell, halfway between these two categories.
For as long as Neuroscience has existed, it has been recognized that the brain works primarily thanks to the neurons and their ability 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. Some of these glial cells, known as astrocytes, intimately surround synapses, the points of contact where neurotransmitters are released to transmit information between neurons.
This is why neuroscientists have long suggested that astrocytes may have an active role in synaptic transmission and participate in information processing.
However, the studies conducted to date to demonstrate this have suffered from conflicting results and have not reached a definitive scientific consensus yet.
By identifying a new cell type with the characteristics of an astrocyte and expressing the molecular machinery necessary for synaptic transmission, neuroscientists from the Department of Basic Neurosciences of the Faculty of Biology and Medicine of the University of Lausanne (UNIL) and the Wyss Center for Bio and Neuroengineering in Geneva put an end to years of controversy.
The Key to the Puzzle
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. 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,” says Ludovic Telley, Assistant professor at UNIL, co-director of the study.
New Functional 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 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,” says Andrea Volterra, honorary professor at UNIL and visiting faculty at the Wyss Center, co-director of the study.
In addition, this 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,” says Roberta de Ceglia, first author of the study and senior researcher at UNIL.
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.
Links With Brain Pathologies
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, whose seizures were exacerbated.
Finally, the study shows that glutamatergic astrocytes also have a role in the regulation of brain circuits involved in movement control and could offer therapeutic targets for Parkinson’s disease.
“In between neurons and astrocytes, we now have a new kind of cell at hand. 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,” projects Andrea Volterra.
Specialized astrocytes mediate glutamatergic gliotransmission in the CNS
Multimodal astrocyte–neuron communications govern brain circuitry assembly and function. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions.
For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons. However, the existence of this mechanism has been questioned owing to inconsistent data and a lack of direct supporting evidence.
Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes and using molecular, bioinformatic and imaging approaches, together with cell-specific genetic tools that interfere with glutamate exocytosis in vivo.
By analysing existing single-cell RNA-sequencing databases and our patch-seq data, we identified nine molecularly distinct clusters of hippocampal astrocytes, among which we found a notable subpopulation that selectively expressed synaptic-like glutamate-release machinery and localized to discrete hippocampal sites.
Using GluSnFR-based glutamate imaging in situ and in vivo, we identified a corresponding astrocyte subgroup that responds reliably to astrocyte-selective stimulations with subsecond glutamate release events at spatially precise hotspots, which were suppressed by astrocyte-targeted deletion of vesicular glutamate transporter 1 (VGLUT1).
Furthermore, deletion of this transporter or its isoform VGLUT2 revealed specific contributions of glutamatergic astrocytes in cortico-hippocampal and nigrostriatal circuits during normal behaviour and pathological processes.
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.