Nature: Newly Discovered Special Neurons - Glutamatergic Astrocytes

Researchers at the University of Lausanne in Switzerland have published a study in the journal Nature titled "Specialized Astrocytes Mediate Glutamatergic Gliotransmission in the CNS."

These specialized cells play a vital role in enhancing memory function, participating in motor control, and safeguarding the central nervous system (CNS), shedding new light on the intricate role of astrocytes in the physiology and pathology of the CNS. They also provide potential targets for the treatment of CNS diseases such as epilepsy, Alzheimer's, Parkinson's, and more.

Multi-modal astrocyte-neuron communication controls the assembly and function of brain circuits. For example, by rapidly releasing glutamate, astrocytes can regulate synaptic network excitability, plasticity, and synchronous activity, but they also contribute to synaptic network dysregulation in neuropsychiatric disorders. For astrocytes to engage in information exchange through fast glutamate release, they must possess Ca2+-dependent exocytotic machinery similar to neurons. However, the existence of this mechanism has been in doubt due to inconsistent research data and a lack of direct supporting evidence.

To confirm whether astrocytes can release neurotransmitters like neurons, the researchers first closely examined the gene expression profile of astrocytes to identify the mechanisms required for the rapid secretion of glutamate, the primary neurotransmitter used by neurons.

Using single-cell transcriptomics, the research team identified nine molecularly distinct subtypes of hippocampal astrocytes, with one particular subtype known as glutamatergic astrocytes, expressing specific synaptic-like glutamate release mechanisms and located at different hippocampal sites. This subtype of astrocytes exhibited the transcription of vesicular glutamate transporter 1 (VGLUT1), a protein responsible for selectively loading glutamate into synaptic vesicles and promoting its release in the synaptic cleft. The study also found that these cells contained other essential proteins for glutamatergic vesicle function and rapid information exchange with other cells.

Fig.1 Cross-species transcriptional convergence of glutamatergic astrocytes identified by scRNA-seq and spatially resolved via RNAscope HiPlex in mouse and human hippocampus.¹

Subsequently, the researchers attempted to confirm the functionality of these unique glutamatergic astrocytes, specifically, whether they could release glutamate at a rate comparable to synaptic transmission. To do this, they used GluSnFR-basedin vivo and in vitro imaging techniques to visualize glutamate vesicle release in brain tissue and live mice.

The results revealed that glutamatergic astrocytes responded to selective stimulation by rapidly releasing glutamate, occurring in spatially segregated regions of the cells, similar to neuronal synapses. Furthermore, glutamate release impacted synaptic transmission and regulated neuronal circuits, as the research team demonstrated by inhibiting the expression of VGLUT in these cells.

The study also found a connection between these glutamatergic astrocytes and brain diseases. By specifically knocking out VGLUT1 in these cells, the research team confirmed the impact of these cells on memory consolidation and observed their association with pathology, such as exacerbating seizures.

Lastly, the research suggests that glutamatergic astrocytes are involved in regulating brain circuits related to motor control, potentially providing new therapeutic targets for Parkinson's disease. The team's future studies will further explore the potential protective role of this cell type in memory loss associated with Alzheimer's disease and its role in other brain regions and diseases.

Reference

1. de Ceglia, Roberta et al. “Specialized astrocytes mediate glutamatergic gliotransmission in the CNS.” Nature. 2023;622(7981):120-129. Distributed under Open Access License CC BY 4.0 without modification.