Central myelinated axons are injured in a variety of conditions including ischemia, trauma and neuroinflammation. Failure of ion pumping in compromised axons leads to Na overload and depolarization (for a recent review see Trapp & Stys, Lancet Neurol., 2009).  As a result, several Na-coupled and electrogenic ion and molecular transporters are stimulated to operate in reverse modes, transporting substances in inappropriate directions leading to damaging accumulation of Ca and neurotransmitters.  For instance Na-Ca exchangers load axons with toxic amounts of Ca, and voltage-gated Ca channels also contribute to intracellular Ca loading.  Importantly, axons contain intracellular Ca stores that are released by depolarization: L-type Ca channels sense voltage changes across the axolemma and in turn activate ryanodine receptors on “axoplasmic reticulum”, releasing toxic amounts of Ca from internal pools, in a manner very similar to “excitation-contraction coupling” Ca release in skeletal muscle.

Recently, studies have identified glutamate receptors on axons and oligodendrocytes, their processes and even inner and outer loops of mature myelin (Micu et al, Nature, 2006; Ouardouz et al., Ann Neurol, 2009a & 2009b). Among them, NMDA receptors require both glutamate and glycine as obligatory co-agonists.  Na-coupled glutamate and glycine transporters, driven in the transmitter efflux mode by axonal Na loading and depolarization, promote excessive activation of receptors and Ca entry into compartments already unable to adequately buffer ionic loads.  Thus, excessive glutamate and glycine release, leading to receptor over-activation, represents a novel and potentially very important mechanism of injury to oligodendrocytes and the myelin sheath; excessive activation of these myelinic receptors may represent one of the most proximal events leading to ischemic and inflammatory demyelination.

In contrast, NMDA receptors do not play an important role in injury to the axon cylinder per se.  Instead, internodal “nanocomplexes” containing AMPA or kainate receptors, Ca channels and nNOS are stimulated leading to ryanodine receptor activation and release of Ca from axonal stores.  This increasingly rich complement of signaling pathways in central myelinated axons and glia may be amenable to pharmaco-modulation in MS and other disorders of central white matter.

In addition to glutamate receptors, noradrenergic receptors of the alpha 2 subtype play a very important role in ischemic white matter damage (Nikolaeva et al., J Neurosci., 2009).  These receptors are present on central myelinated axons and mediate axonal Na and Ca overload, as well as functional injury.  Norepinephrine appears to be released by reversal of the Na-dependent norepinephrine transporter.  Unexpectedly, this transporter appears to be expressed in the myelin sheath, rather than the axon cylinder, suggesting that myelin can both take up and release transmitter depending on the prevailing ionic gradients.

The goal of our lab is to gain a detailed fundamental understanding of the many molecular pathways that are triggered during pathophysiological conditions, in order to be able to devise effective therapeutic strategies for the many human disorders that adversely affect central white matter tracts and peripheral nerves.

The goal of our lab is to gain a detailed fundamental understanding of the many molecular pathways that are triggered during pathophysiological conditions, in order to be able to devise effective therapeutic strategies for the many human disorders that adversely affect central white matter tracts and peripheral nerves.