Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication

Abstract

Neuronal activity provokes myelinating oligodendrocytes to release exosomes by stimulation of ionotropic glutamate receptors, and that once released, these vesicles are internalized by neurons conveying neuroprotection.

Abstract

Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca ²⁺ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity.

Author Summary

Brain function largely depends on the communication between electrically excitable neurons and surrounding glial cells. Myelinating oligodendrocytes are a type of brain cell that insulate major neuronal processes (axons) and help to sustainably maintain axonal health, which is poorly understood in molecular terms. Several cell types release microvesicles termed exosomes that include genetic information (primarily RNA) and can act as vehicles transferring specific cargo to target cells. Here, we demonstrate that exosomes secreted by oligodendrocytes in response to neuronal signals enter neurons to make their cargo functionally available to the neuronal metabolism. We revealed in cultured cells that exosome release from oligodendrocytes is triggered by the neurotransmitter glutamate through activation of ionotropic glutamate receptors. We also show that glial exosomes are internalized by neurons via an endocytic pathway. By modifying oligodendroglial exosomes with a reporter enzyme, we could demonstrate that the exosome cargo is recovered by target neurons in culture as well as in vivo after injection of exosomes into the mouse brain. Neurons challenged with stressful growth conditions were protected when treated with oligodendroglial exosomes. The study introduces a new concept of reciprocal cell communication in the nervous system and identifies the signal-mediated transfer of exosomes from oligodendrocytes to neurons contributing to the preservation of axonal health.