Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS

Abstract

Astroglia play active and diverse roles in modulating neuronal/synaptic functions in the CNS. How these astroglial functions are regulated, especially by neuronal signals, remains largely unknown. Exosomes, a major type of extracellular vesicles (EVs) that originate from endosomal intraluminal vesicles (ILVs), have emerged as a new intercellular communication process. By generating cell-type-specific ILVs/exosome reporter (CD63-GFPf/f) mice and immuno-EM/confocal image analysis, we found that neuronal CD63-GFP+ ILVs are primarily localized in soma and dendrites, but not in axonal terminals in vitro and in vivo. Secreted neuronal exosomes contain a subset of microRNAs (miRs) that is distinct from the miR profile of neurons. These miRs, especially the neuron-specific miR-124-3p, are potentially internalized into astrocytes. MiR-124-3p further up-regulates the predominant glutamate transporter GLT1 by suppressing GLT1-inhibiting miRs. Our findings suggest a previously undescribed neuronal exosomal miR-mediated genetic regulation of astrocyte functions, potentially opening a new frontier in understanding CNS intercellular communication.

Fibroblast Growth Factor 2‐Mediated Regulation of Neuronal Exosome Release Depends on VAMP3/Cellubrevin in Hippocampal Neurons

“…Although providing new insights into the molecular mechanism of neuronal exosome release, the translational potential of our results is limited by the lack of in vivo data. Therefore, future studies will have to confirm our results in vivo, for example, by using suitable reporter animal models that have been published recently . It would be interesting to determine, if EV release exhibits short‐ or long‐term changes through electrical stimulation in vivo, like this is known to be the case for hippocampal synaptic transmission (i.e., long‐term potentiation).…”

“…In the central nervous system (CNS), EVs released by neurons and glial cells contribute to the complex networks of cell‐to‐cell signals that underlie CNS physiology and pathology . Emerging evidence indicates that EV‐mediated signaling regulates neuronal firing, synaptic plasticity, and myelin formation .…”

“…Neuronal depolarization and glutamate release has been suggested to stimulate the secretion of exosomes from neurons and oligodendrocytes while serotonin is reported to stimulate microglial secretion of EVs . The EVs may in turn transfer bioactive RNAs, proteins, and lipids between cells, thereby regulating neuronal activity . Similar to neurotransmitter vesicles fusing with the PM, exosome release can be evoked by electrical activity in conjunction with calcium influx and depends on SNARE proteins.…”

Gliomas Interact with Non-glioma Brain Cells via Extracellular Vesicles

“…CD63 is a specific membrane protein of EVs (Escola et al, 1998). To label EVs in cells, we infected 73C glioma cells with lentivirus (LV)-CD63-GFP, which we used for labeling the EV membrane, as previously reported (Men et al, 2019). After co-culturing these glioma cells in transwells with primary astrocytes below the transwells ( Figure S5), we detected GFP + EVs from astrocytes.…”

NK cell-derived exosomes carry miR-207 and alleviate depression-like symptoms in mice

“…Exosomes are particles of approximately 50-150 nm in diameter [18] that exist in the blood and other body fluids. They are released from many types of tissues.…”