Age-specific localization of NMDA receptors on oligodendrocytes dictates axon function recovery after ischemia

Abstract

Oligodendrocytes and axons are the main targets of an ischemic white matter injury and the resultant loss of axon function underlies the clinical disability in patients who survive a stroke. The cellular mechanisms of ischemic injury change as a function of age in concordance with age-mediated structural changes in white matter. Shorter periods of injury cause rapid and robust loss of axon function together with widespread oligodendrocyte death. While blockade of NMDA receptors fails to benefit axon function, removal of extracellular Ca2+ during ischemia remarkably promotes axon function recovery in young white matter. However, these same approaches hinder axon function recovery and fail to protect oligodendrocytes in aging white matter. The obligatory GluN1 subunit of the NMDA receptor exhibits an age-specific expression pattern such that in young adult white matter, it is mostly localized on oligodendrocyte cell bodies, while in aging white matter, it is also observed on myelin processes. This age-dependent re-localization and redistribution pattern mimics GluN1 expression observed during development, but in reverse order. During development, GluN1 immunoreactivity traffics from astrocytes at postnatal day 4-11 (P4-11) to myelin processes at P12-18 and to oligodendrocytes cell bodies at P19-21. Although immature axons are more resistant to ischemia, blockade of NMDA receptors during ischemia at P4-11 and P12-18 worsens axon function recovery and fails to benefit axons at P19-21. Thus, age-specific expression patterns of NMDA receptor localization may seem to modulate the plasticity of oligodendrocytes and myelin in response to ischemia as a function of age in white matter.

A single‐cell analysis reveals multiple roles of oligodendroglial lineage cells during post‐ischemic regeneration

“…GS in OLs could also play a role in the regulation of myelination, since the overexpression of GS in Schwann cells was shown to enhance myelin production (Saitoh and Araki, 2010). Besides, it may explain the failure of NMDA antagonists in stroke clinical trials, as the blockage of OLs NMDA receptors worsens axons functional recovery (Baltan, 2016). Here, we detected the expression of glutamate receptors predominantly in NG2 cells.…”

“…Such dramatic difference between gray and white matter OLs points to a region-specific glutamate regulation of axon-myelin interactions. Besides, it may explain the failure of NMDA antagonists in stroke clinical trials, as the blockage of OLs NMDA receptors worsens axons functional recovery (Baltan, 2016). Another interesting observation was the different expression of Grm3/5.…”

Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter

“…It is likely that aging, as a result of lower calreticulin and calnexin levels, impairs SER Ca 2ϩ homeostasis (Coe and Michalak, 2009) and impedes aging axon function recovery following OGD (Baltan et al, 2008;Baltan, 2015). This is an appealing suggestion particularly because removal or attenuation of Ca 2ϩ influx confers complete protection to axon function in young MONs after OGD (60 min) becomes ineffective or injurious in MONs from 12-month-old mice, even after short durations of OGD (30 -45 min; Baltan et al, 2008).…”

“…Although these results suggest that individual mitochondria become elongated with age, we further evaluated axonal ultrastructural changes using 3-D EM to determine a structure-function basis for age-related alterations in molecular architecture and response to ischemia (Baltan, 2012(Baltan, , 2015. Since 12 months of age marks the beginning of increased sensitivity to ischemic injury (Baltan et al, 2008;, our 3-D EM studies primarily compared MONs at 1 and 12 months (Fig.…”

Protecting Oligodendrocytes by Targeting Non-Glutamate Receptors as a New Therapeutic Strategy for Ischemic Stroke

“…Emerging data suggests that the activation of OLG NMDA receptors is not likely contributing to WM damage, and blocking NMDA receptors provided no protection in ischemic WM injury [18,19]. What is more, individual evidence even confirmed that blocking NMDA receptors may actually worsen the functional outcome of aging in WM in response to ischemia [20]. Besides those mentioned above, the views concerning the role of non-NMDA receptors such as the AMPA/kainate glutamate receptor in ischemic OLG damage are also conflicting [21].…”