The effect of N-acetyl-aspartyl-glutamate and N-acetyl-aspartate on white matter oligodendrocytes

Abstract

Elevations of the levels of N-acetyl-aspartyl-glutamate (NAAG) and N-acetyl-aspartate (NAA) are associated with myelin loss in the leucodystrophies Canavan's disease and Pelizaeus-Merzbacher-like disease. NAAG and NAA can activate and antagonize neuronal N-methyl-D-aspartate (NMDA) receptors, and also act on group II metabotropic glutamate receptors. Oligodendrocytes and their precursors have recently been shown to express NMDA receptors, and activation of these receptors in ischaemia leads to the death of oligodendrocyte precursors and the loss of myelin. This raises the possibility that the failure to develop myelin, or demyelination, occurring in the leucodystrophies could reflect an action of NAAG or NAA on oligodendrocyte NMDA receptors. However, since the putative subunit composition of NMDA receptors on oligodendrocytes differs from that of neuronal NMDA receptors, the effects of NAAG and NAA on them are unknown. We show that NAAG, but not NAA, evokes an inward membrane current in cerebellar white matter oligodendrocytes, which is reduced by NMDA receptor block (but not by block of metabotropic glutamate receptors). The size of the current evoked by NAAG, relative to that evoked by NMDA, was much smaller in oligodendrocytes than in neurons, and NAAG induced a rise in [Ca2+]i in neurons but not in oligodendrocytes. These differences in the effect of NAAG on oligodendrocytes and neurons may reflect the aforementioned difference in receptor subunit composition. In addition, as a major part of the response in oligodendrocytes was blocked by tetrodotoxin (TTX), much of the NAAG-evoked current in oligodendrocytes is a secondary consequence of activating neuronal NMDA receptors. Six hours exposure to 1 mM NAAG did not lead to the death of cells in the white matter. We conclude that an action of NAAG on oligodendrocyte NMDA receptors is unlikely to be a major contributor to white matter damage in the leucodystrophies.

Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration

“…Impaired NAAG signaling has been implicated in schizophrenia and some studies have suggested NAAG plays a role in antipsychotic drug mechanisms of action (Ghose et al, 2009; Olszewski et al, 2012; Jessen et al, 2013). Of particular relevance to our current study, elevated NAAG has been associated with hypomyelination disorders such as Canavan's disease and Pelizaeus-Merzbacher disease (PMD) (Kolodziejczyk et al, 2009). Symptoms of these disorders include a diminished motor control.…”

Activation of sodium‐dependent glutamate transporters regulates the morphological aspects of oligodendrocyte maturation via signaling through calcium/calmodulin‐dependent kinase IIβ's actin‐binding/‐stabilizing domain

“…Such changes in glutamate homeostasis have been implicated in mediating excitotoxicity (Matute 2011; Pitt et al 2003). However, it has also been suggested that mature rodent as well as human oligodendrocytes are largely resistant to such glutamate-mediated injury (Kolodziejczyk et al 2009; Rosenberg et al 2003; Wosik et al 2004). Thus, and in light of our findings, it is tempting to speculate that changes in glutamate homeostasis and sodium-dependent glutamate transporter signaling may primarily contribute to the differentiation block seen in MS rather than mediate oligodendrocyte cell death.…”

Elevated CSF N -acetylaspartylglutamate in patients with free sialic acid storage diseases

“…NAAG was indeed recently reported to have a negligible action on oligodendrocytes' NMDA receptors. 9 The increase of NAAG in the extracellular space resulting from inhibition of GCPII has also been shown to be neuroprotective. 10 In patients with undiagnosed leukodystrophies, increased free sialic acid in CSF or urine suggests the diagnosis of SASD.…”