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  • br The concept of the axo myelin synapse

    2022-06-23


    The concept of the axo-myelin ‘synapse’ Axons can release glutamate in a Ca+-dependent and independent manner (reviewed in [13,69]). Glutamate released from axons activates GluRs located in myelin, a feature that gave rise to the idea of the axo-myelin ‘synapse’ by analogy with classical synaptic communication between neurons (reviewed in [69]). Thus, depolarization of the axolemma in myelinated axons during HS-173 propagation may result in glutamate release by reversal of glutamate transport and/or exocytosis triggered by Ca+-induced Ca+ release from the axoplasmic reticulum. Glutamate in the periaxonal space can activate AMPA and NMDA receptors in the myelin sheath that recruit glucose transporters to the oligodendrocyte membrane increasing glucose uptake, glycolysis and ultimately the production of pyruvate and lactate by these cells ([89]. Pyruvate fuels mitochondria in oligodendrocytes and myelin whereas lactate is shuttled via monocarboxylate transporters to the axon as an energy substrate for aerobic metabolism to support ATP demand by Na+/K+-ATPase [89]. Notably, this glutamatergic axo-myelin ‘synapse’ may behave as a power switch to energize axons on demand to control metabolic cooperation between oligodendrocytes and axons. Signalling at the axo-myelin ‘synapse’ may have pathological consequences in acute and chronic conditions [69]. Thus, shortage of glucose during ischemia interrupts the supply of lactate from oligodendrocytes to mitochondria in axons and, consequently, induces a reduction in axonal ATP that may impair ion transporter function causing depolarization and Ca2+ overload of the cytosol. Glutamate may also be released from exhausted axons and thus contributes to excessive activation of GluRs in enwrapping myelin and leads to Ca2+-dependent activation of proteases, phospholipases and deiminases that disrupt myelin sheaths generating lipid debris and triggering an adaptive immune response. Recent evidence has shown ischemic release of glutamate from axoplasmic vesicles, leading to accumulation of the neurotransmitter under the myelin and in the extracellular space [29]. This pathway is particularly significant for pathogenic activation of myelinic NMDA GluRs and rapid myelin damage.
    Glutamate receptor types and expression in WM Glutamate can activate ionotropic receptors and/or metabotropic receptors, which are coupled to G proteins (for reviews, see Refs. [66,106]. Both ionotropic and metabotropic GluRs are expressed in glial cells in WM (for recent reviews, see Refs. [6,63]. In particular, astrocytes of the optic nerve respond to glutamate via AMPA- and NMDA-type receptors as well as on group I mGlu receptors to induce an increase in [Ca2+]i which leads to the release of ATP by a mechanism involving P2 × 7 receptors [45]. Similarly, oligodendrocytes express functional AMPA and kainate type receptors throughout a wide range of developmental stages and species, including humans [65]. In addition, immature and mature oligodendrocytes express NMDA (N-methyl-d-aspartate) receptors, which can be activated during injury [7,57,68,92]. Moreover, oligodendrocytes also express receptors from all three groups of metabotropic glutamate receptors, although the expression level of these receptors is developmentally regulated and is very low in mature oligodendrocytes [23]. In turn, WM oligodendrocyte progenitors, or NG2 cells, also express AMPA-type glutamate receptors which can be activated by glutamate released from mechanically activated astrocytes and from axons during action potential passage [46]. In contrast, little is known about GluRs in WM microglia, although glutamate is involved in the transmission of death signals to microglia which respond by migrating to sites of neuronal injury [97]. In gray matter, ramified microglia may express AMPA and metabotropic glutamate receptors which can promote inflammation, chemotaxis, neuroprotection or neurotoxicity (for reviews see Refs. [82,27].