Abstract
Glutamate signaling may orchestrate oligodendrocyte precursor cell (OPC) development and myelin regeneration through the activation of glutamate receptors at OPC‐neuron synapses. D‐Aspartate is a D‐amino acid exerting modulatory actions at glutamatergic synapses. Chronic administration of D‐Aspartate has been proposed as therapeutic treatment in diseases related to myelin dysfunction and NMDA receptors hypofunction, including schizophrenia and cognitive deficits. Here, we show, by using an in vivo remyelination model, that administration of D‐Aspartate during remyelination improved motor coordination, accelerated myelin recovery, and significantly increased the number of small‐diameter myelinated axons. Chronically administered during demyelination, D‐Aspartate also attenuated myelin loss and inflammation. Interestingly, D‐Aspartate exposure stimulated OPC maturation and accelerated developmental myelination in organotypic cerebellar slices. D‐Aspartate promoting effects on OPC maturation involved the activation of glutamate transporters, AMPA and NMDA receptors, and the Na+/Ca2+ exchanger NCX3. While blocking NMDA or NCX3 significantly prevented D‐Aspartate‐induced [Ca2+]i oscillations, blocking AMPA and glutamate transporters prevented both the initial and oscillatory [Ca2+]i response as well as D‐Aspartate‐induced inward currents in OPC. Our findings reveal that D‐Aspartate treatment may represent a novel strategy for promoting myelin recovery.
Highlights
A significant interest in new multiple sclerosis (MS) therapeutics is the identification of novel pharmacological compounds able to stimulate the remyelination process by boosting oligodendrocyte precursors cells (OPC) to form new myelin before axons become irreversibly damaged (Franklin & Ffrench-Constant, 2017)
The present study shows that D-Aspartate treatment stimulates the maturation of oligodendrocyte precursor cells, attenuates demyelination, and enhances remyelination in the cuprizone mouse model of myelin damage and repair
While blockade of amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) or NMDA receptors or NCX3 exchanger significantly prevented D-Asp-induced [Ca2+]i oscillations but only partially affected the initial [Ca2+]i rise, we found that blocking glutamate transporters completely prevented both the initial and oscillatory [Ca2+]i response in primary OPC
Summary
A significant interest in new multiple sclerosis (MS) therapeutics is the identification of novel pharmacological compounds able to stimulate the remyelination process by boosting oligodendrocyte precursors cells (OPC) to form new myelin before axons become irreversibly damaged (Franklin & Ffrench-Constant, 2017). Demyelinated axons, when still active, by releasing glutamate at OPC-neuron synapse may instruct OPC to differentiate into new myelinating oligodendrocytes (Bergles et al, 2000; Lundgaard et al, 2013; Micu et al, 2017). In this regard, glutamate signaling through a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) and N-Methyl-D-Aspartate (NMDA) receptors has garnered the main interest as inductive signal prompting OPC to differentiate and remyelinate (Yuan et al, 1998; Li et al, 2013; Fannon et al, 2015; Gautier et al, 2015). In line, mounting evidence suggests that the activation of Ca2+-dependent pathways through glutamate receptors or the Na+/Ca2+ exchanger NCX3 may influence oligodendrocyte maturation, myelin synthesis, and remyelination processes (Boscia et al, 2012, 2016a; Martinez-Lozada et al, 2014; Casamassa et al, 2016; Friess et al, 2016)
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