Glutamate-induced white matter injury: Excitotoxicity without synapses

White matter of the brain and spinal cord is irreversibly damaged by ischemia and trauma. Recent evidence indicates that despite the absence of synaptic elements, excitotoxic mechanisms play an important role in the pathogenesis of white matter damage. Glial cells, including astrocytes and oligodendrocytes, possess non-NMDA glutamate receptors and are injured by excessive exposure to AMPA/kainate agonists. In addition, the myelin sheath itself appears to respond directly to glutamate stimulation via AMPA receptors, which may also lead to injury of this key constituent of myelinated axons. During white matter anoxia/ischemia or trauma, endogenous glutamate is released mainly from axoplasmic pools in a nonvesicular fashion through Na+-dependent glutamate transporters, stimulated to operate in the glutamate efflux mode by collapse of transmembrane ion gradients and depolarization. It appears that parallel mechanisms are triggered by injurious stimuli, involving reverse Na+-Ca2+ exchange and voltage-gated Ca2+ channels producing Ca2+ overload of the axon cylinder, whereas glutamate release with AMPA receptor overactivation causes Ca2+-dependent damage to the ensheathing myelin and supporting glia. The emerging complexity of white matter injury mechanisms requires a thorough understanding of the interrelated steps to optimize therapeutic design.