D‐Aspartate treatment attenuates myelin damage and stimulates myelin repair

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 + /Ca 2+ exchanger NCX3. While blocking NMDA or NCX3 significantly prevented D‐Aspartate‐induced [Ca 2+ ] i oscillations, blocking AMPA and glutamate transporters prevented both the initial and oscillatory [Ca 2+ ] 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. Synopsis Glutamate signaling is critical for oligodendrocyte precursor cell (OPC) repair responses. D‐Aspartate exerts modulatory actions at glutamatergic synapses. D‐Aspartate treatment is here shown to stimulate oligodendrocyte development and benefits demyelination and remyelination processes in vivo . D‐Aspartate exposure promoted OPC maturation and stimulated developmental myelination in organotypic cerebellar slices. D‐Aspartate treatment attenuated demyelination and accelerated remyelination in the cuprizone mouse model of myelin damage and repair. D‐Aspartate boosting effects on OPC differentiation involved an orchestrated stimulation of calcium signalling pathways that are consequent to a cooperative activation of glutamate transporters and AMPA receptors, which then leads to a secondary NMDA receptor and NCX3 exchanger effects. Graphical Abstract Glutamate signaling is critical for oligodendrocyte precursor cell (OPC) repair responses. D‐Aspartate exerts modulatory actions at glutamatergic syna