1. Ottawa Health Research Institute, Division of Neuroscience and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1Y 4K9, Canada
2. Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
3. Department of Physiology and Biophysics, Hotchkiss Brain Institute, University of Calgary, Alberta T2N 4N1, Canada

Correspondence to: P. K. Stys¹ Correspondence and requests for materials should be addressed to P.K.S. (Email: pstys@ohri.ca).

Abstract

Central nervous system myelin is a specialized structure produced by oligodendrocytes that ensheaths axons, allowing rapid and efficient saltatory conduction of action potentials¹. Many disorders promote damage to and eventual loss of the myelin sheath, which often results in significant neurological morbidity. However, little is known about the fundamental mechanisms that initiate myelin damage, with the assumption being that its fate follows that of the parent oligodendrocyte. Here we show that NMDA (N-methyl-d-aspartate) glutamate receptors mediate Ca²⁺ accumulation in central myelin in response to chemical ischaemia in vitro. Using two-photon microscopy, we imaged fluorescence of the Ca²⁺ indicator X-rhod-1 loaded into oligodendrocytes and the cytoplasmic compartment of the myelin sheath in adult rat optic nerves. The AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor antagonist NBQX² completely blocked the ischaemic Ca²⁺ increase in oligodendroglial cell bodies, but only modestly reduced the Ca²⁺ increase in myelin. In contrast, the Ca²⁺ increase in myelin was abolished by broad-spectrum NMDA receptor antagonists (MK-801, 7-chlorokynurenic acid, d-AP5^{3, 4}), but not by more selective blockers of NR2A and NR2B subunit-containing receptors (NVP-AAM077⁵ and ifenprodil^{2, 4}). In vitro ischaemia causes ultrastructural damage to both axon cylinders and myelin⁶. NMDA receptor antagonism greatly reduced the damage to myelin. NR1, NR2 and NR3 subunits were detected in myelin by immunohistochemistry and immunoprecipitation, indicating that all necessary subunits are present for the formation of functional NMDA receptors. Our data show that the mature myelin sheath can respond independently to injurious stimuli. Given that axons are known to release glutamate^{7, 8, 9}, our finding that the Ca²⁺ increase was mediated in large part by activation of myelinic NMDA receptors suggests a new mechanism of axo–myelinic signalling. Such a mechanism may represent a potentially important therapeutic target in disorders in which demyelination is a prominent feature, such as multiple sclerosis, neurotrauma, infections (for example, HIV encephalomyelopathy) and aspects of ischaemic brain injury.

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