Fig. 1
A Example 2-photon micrograph of mouse optic nerve whose myelin was labeled with the green lipophilic dye DiOC6 together with the Ca indicator Xrhod-1. Individual myelin sheaths are readily visible (arrows). B Myelinic Ca levels increased substantially by removal of free Cu ions with BCS. This effect was blocked by the broad spectrum NMDAR antagonist DCKA (50 µM). C Quantitative result showing how excess Cu or NMDAR blockade (DCKA) prevented BCS-induced Ca increase. Selective antagonism with GluN2A & B-containing NMDARs with ifenprodil and NVP-AAM077 was not effective. D Activating NMDARs with D-serine and NMDA failed to induce a Ca rise in WT optic nerve. In contrast, PrP-lacking myelin exhibited a substantial Ca increase in response to a glycine site agonist alone (D-serine, 10 µM), which increased further with addition of NMDA (500 µM). These responses were completely blocked by DCKA confirming the major contribution of NMDARs. E, F Aβ1-42 also caused a substantial myelinic Ca increase which could be overcome by excess Cu ions or NMDAR antagonists. Taken together, these data indicate that myelinic NMDARs can admit substantial amounts of Ca, and their activity is potently modulated by micromolar Cu and prion protein. The effect of exogenous Aβ1–42 has implications for white matter pathology frequently seen in Alzheimer's disease (*P < 0.01, Dunn's Many-to-One Rank Comparison Test)