NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia

Abstract

Central nervous system myelin is a specialized structure produced by oligodendrocytes that ensheaths axons, allowing rapid and efficient saltatory conduction of action potentials. 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 (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor antagonist NBQX 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), but not by more selective blockers of NR2A and NR2B subunit-containing receptors (NVP-AAM077 and ifenprodil). In vitro ischaemia causes ultrastructural damage to both axon cylinders and myelin. 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, 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.

Functional glutamate transport in rodent optic nerve axons and glia

“…Expression of AMPA/kainate receptors is particularly marked in immature cells of the oligodendrocyte lineage (Itoh et al, 2002), which in the neonatal optic nerve are in the process of forming an exquisitely close morphological arrangement with neighbouring axons (Butt and Ransom, 1993). We and others have recently demonstrated the presence of functional NMDA-type glutamate receptors in oligodendrocyte processes (Salter and Fern, 2005;Káradóttir et al, 2005;Micu et al, 2006)). The activation of these receptors is likely to be important in a variety of diseases and must have significant developmental consequences.…”

NMDA receptor blockage with 2-amino-5-phosphonovaleric acid improves oxidative stress after spinal cord trauma in rats

“…N-methyl-D-aspartate (NMDA) glutamate receptors mediate Ca 2 þ accumulation in central myelin in response to chemical ischemia in vitro. 5 A prolonged activation of these receptors leads to increased intracellular concentrations of sodium, potassium and/or calcium ions. These changes in ionic gradients initiate a sequence of events that ultimately lead to cell death.…”

Glia as transmitter sources and sensors in health and disease

“…Conversely in periventricular white matter of neonatal rat, hypoxia-ischemia produces a significant depletion of oligodendroglial glutamate indicative of net release (Back et al, 2006), while in cell culture these cells release glutamate that can activate receptors on the host cell and its neighbours resulting in acute injury (Fern & Moller, 2000). The significance of NMDA (Karadottir et al, 2005;Salter & Fern, 2005;Micu et al, 2006) and non-NMDA (McDonald et al, 1998;Fern & Moller, 2000;Follett et al, 2000) glutamate receptors for oligodendroglia injury has been confirmed in a variety of preparations, but the significance of glutamate release from oligodendroglial cells themselves vs., release from astrocytes or axons (Kukley et al, 2007;Ziskin et al, 2007;Alix et al, 2008;Arranz et al, 2008) is not clear.…”

“…Astrocytes are also replete with glutamate sensors such as ionotropic and metabotropic glutamate receptors (see Gallo & Ghiani, 2000), and are decorated with potential glutamate release mechanisms. While the physiological function(s) of glutamate release and reception in astrocytes is a matter of debate, it is clear that excessive glutamate release is associated with injury in disease states ranging from ischemic lesions such as stroke (see Hazell, 2007) including white matter injury (Karadottir et al, 2005;Salter & Fern, 2005;Micu et al, 2006), through demylinating disorders like multiple sclerosis (Pitt et al, 2000) to dementias such as Alzheimer's and Huntington's diseases (see Mattson, 2008). The acute injury associated with excess glutamate release is mediated by a well-characterized excitotoxic cascade involving synaptic exocytosis, depolarization and further synaptic release.…”