TRPA1 block protects against loss of white matter function during ischaemia in the mouse optic nerve

Abstract

AbstractOligodendrocytes produce myelin which provides insulation to axons and speeds up neuronal transmission. In ischaemic conditions myelin is damaged, resulting in mental and physical disabilities. Therefore, it is important to understand how the function of oligodendrocytes and myelin is affected by ischaemia. Recent evidence suggests that oligodendrocyte damage during ischaemia is mediated by TRPA1, whose activation raises intracellular Ca2+ concentrations and damages compact myelin. Here, we show that TRPA1 is constitutively active in oligodendrocytes and the optic nerve, as the specific TRPA1 antagonist, A-967079, decreases basal oligodendrocyte Ca2+ concentrations and increases the size of the compound action potential. Conversely, TRPA1 agonists reduce the size of the optic nerve compound action potential, and this effect is significantly reduced by the TRPA1 antagonist. These results indicate that glial TRPA1 regulates neuronal excitability in the white matter under physiological as well as pathological conditions. Importantly, we find that inhibition of TRPA1 prevents loss of compound action potentials during oxygen and glucose deprivation (OGD) and improves the recovery. TRPA1 block was effective when applied before, during or after OGD, indicating that the damage is occurring during ischaemia and during the recovery, but importantly, that therapeutic intervention is possible after the ischaemic insult. These results indicate that TRPA1 has an important role in the brain, and that its block may be effective in treating oligodendrocyte loss and damage in many white matter diseases.