Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation

Abstract

Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell-cell communication in the nervous system. We have shown that exosomes released from oligodendrocytes upon stimulation with the neurotransmitter glutamate are internalized by neurons and enhance the neuronal stress tolerance. Here, we demonstrate that oligodendroglial exosomes also promote neuronal survival during oxygen-glucose deprivation, a model of cerebral ischaemia. We show the transfer from oligodendrocytes to neurons of superoxide dismutase and catalase, enzymes which are known to help cells to resist oxidative stress. Additionally, we identify various effects of oligodendroglial exosomes on neuronal physiology. Electrophysiological analysis using in vitro multi-electrode arrays revealed an increased firing rate of neurons exposed to oligodendroglial exosomes. Moreover, gene expression analysis and phosphorylation arrays uncovered differentially expressed genes and altered signal transduction pathways in neurons after exosome treatment. Our study thus provides new insight into the broad spectrum of action of oligodendroglial exosomes and their effects on neuronal physiology. The exchange of extracellular vesicles between neural cells may exhibit remarkable potential to impact brain performance.

Extracellular vesicles and intercellular communication within the nervous system

“…Mature oligodendrocytes, which are responsible for myelination of neurons in the brain, release EVs in response to glutamate acting on NMDA and AMPA receptors (9,45). Oligodendrocyte-derived EVs carry not only specific myelin proteins, such as major myelin proteolipid protein (14), but also other proteins and RNA related to myelination.…”

“…This downregulation continues until neurons counteract this inhibitory signal- (21); (ii) EVs from microglia increase neuronal synaptic activity, and (iii) neuron-derived EVs activate glial cell functions, such as microglia phagocytosis for clearance of inactive synapses and toxic proteins (44,148). (iv) EVs from oligodendrocytes enhance stress tolerance of neurons, stimulate anterograde transport of signaling molecules in neurons, and carry proteolipoprotein (PLP), which is important for myelination (9,45). (v) Immature neural progenitor cells release proteins, such as the L1 adhesion molecule, the glycosylphosphatidyl-inositol-anchored (GPI-anchored) prion protein, and the GluR2/3 subunit of the glutamate receptor, via EVs, which participate in early brain development (7).…”

Regulation of neuronal excitability by release of proteins from glial cells

“…Furthermore, unconventional mechanisms of membrane translocation have been discovered for FGF-2 [62], which could also apply to its release from astrocytes. Finally, neuron-glia interactions have also been shown to involve the exchange of exosomes, shed from the membranes of donor cells and then internalized by the acceptor cells [63,64].…”

Introduction

“…-the clinical use of exosome cargo analysis in a diagnostic and biomarker capacity, and of exosomes themselves in therapy [14]; -the modulation of mRNA stability during synaptic plasticity involving 3 0 -UTRs and specific miRNAs regulating networks of genes important for neural plasticity and development [15]; -the action of exosomes derived from oligodendroglia on neurons involving redox mechanisms, the modulation of neuronal firing rates and the differential expression of genes and altered signal transduction pathways [16]; -the role of maternal care on the epigenetic state and transcriptional activity of the glucocorticoid receptor in the fetal hippocampus and its molecular mechanism [17]; and -a detailed analysis of the role of microRNAs in synaptogenesis specific to the neuromuscular junction in Drosophila via the coordinated regulation of pre-and post-synaptic cell adhesion molecules [18].…”