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Regulation of developing myelin sheath elongation by oligodendrocyte calcium transients in vivo

Abstract

How action potentials regulate myelination by oligodendrocytes is uncertain. We show that neuronal activity raises [Ca2+]i in developing oligodendrocytes in vivo and that myelin sheath elongation is promoted by a high frequency of [Ca2+]i transients and prevented by [Ca2+]i buffering. Sheath elongation occurs ~1 h after [Ca2+]i elevation. Sheath shortening is associated with a low frequency of [Ca2+]i transients but with longer duration [Ca2+]i bursts. Thus, [Ca2+]i controls myelin sheath development.

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Fig. 1: Calcium transient properties change during oligodendrocyte development.
Fig. 2: Neuronal activity evokes half the calcium transients in developing oligodendrocytes.
Fig. 3: Myelin sheath elongation is regulated by calcium transient rate.

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Acknowledgements

We thank I.L. Arancibia-Carcamo, I. Bianco, E. Dreosti, V. Kyrargyri and W.T. Sherlock for comments, and we thank Fish Facility personnel for care of fish. This work was supported by a Wellcome Trust 4-year PhD studentship (099691/Z/12/Z) to A.M.K., an EU Marie Curie Fellowship (623714) to M.C.F., Wellcome Trust Investigator Awards to D.A. (099222/Z/12/Z) and S.W.W. (104682/Z/14/Z) and an MRC Programme grant (MR/L003775/1) to S.W.W. and G. Gestri.

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Contributions

The work was conceived by A.M.K. and D.A. A.M.K. generated the transgenic lines with help from L.E.V. A.M.K. devised and performed imaging and some electrophysiological experiments with advice from L.E.V. and S.W.W. M.C.F. devised methods for electrical stimulation and whole-cell patch-clamping and performed electrophysiology, whole-cell patch-clamping experiments and some other imaging experiments. A.M.K., M.C.F. and D.A. analyzed the data. S.W.W. and D.A. provided zebrafish, imaging and electrophysiology resources. D.A. and A.M.K. wrote the manuscript, with input from all authors.

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Correspondence to Anna M. Krasnow or David Attwell.

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Integrated Supplementary Information

Supplementary Figure 1 Synchronicity of [Ca2+]i transients in different cell regions

(a-c) Charts: Fraction of time (Probability) that the number of processes on the abscissa (N) had a simultaneous [Ca2+]i elevation, in (a) pre-OLs, (b) early-OLs and (c) OLs from 5, 6 and 6 animals respectively (mean values, shown as horizontal lines with SEM bars, that are below all visible individual data points reflect some data points being zero and hence not plotted on the logarithmic scale charts). Inset tables: Observed distribution of probability as in main graphs, and predicted distribution calculated as follows. If the probability of a single observed process having a high [Ca2+]i is denoted p 1 (this was derived experimentally for each process and averaged over all the processes of each individual cell), and there are N processes, the probability of k processes exhibiting calcium transients simultaneously is: \(p\left(k\right)=\frac{N!{p}_{1}^{k}{(1-{p}_{1})}^{N-k}}{k!\left(N-k\right)!}\). These are the predicted values in the inset tables, when averaged over all cells. The observed values for the fraction of time that 2 or more processes simultaneously showed a high [Ca2+]i were greater than predicted for pre-OLs and early-OLs, implying cooperativity of transient generation between processes or propagation of transients from one process into another, but not for OLs (see 2-sided Chi-squared p values for inset tables). (d-f) Probabilities of N (abscissa) processes having high [Ca2+]i simultaneously and having the soma [Ca2+]i low (black bars) or high (i.e. during a soma [Ca2+]i transient, grey bars), for each of the 3 classes of cell. (g-i) Cumulative probability distributions for the data in d-f, with p values from Kolmogorov-Smirnov tests comparing the distributions for each cell class. When the soma [Ca2+]i was high in early-OLs, there was a larger probability for 1 or more processes to have an elevated [Ca2+]i, than was the case when the soma [Ca2+]i was low. Soma transients occurred with a probability of 0.10, 0.08 and 0.02 for pre-OLs, early-OLs and OLs, respectively, and so the majority of [Ca2+]i transients in processes occurred when soma [Ca2+]i was low. In OLs in particular, processes only showed [Ca2+]i elevations when the soma [Ca2+]i was low, and the data in panel c imply that [Ca2+]i transients in different myelin sheaths are independent of each other. (j-l) Probability of the soma [Ca2+]i being high when the number of processes on the abscissa simultaneously exhibited high [Ca2+]i for each of the 3 classes of cell. For pre-OLs the probability of the soma [Ca2+]i being high is increased when more processes have a simultaneously high [Ca2+]i (p=0.0024, ANOVA) indicating that gene expression might be controlled by somatic [Ca2+]i elevations triggered by simultaneous activity-evoked transients in several processes on the same developing oligodendrocyte. For early-OLs the increase of probability with number of processes simultaneously exhibiting high [Ca2+]i did not reach significance (p=0.86, Kruskal-Wallis test). For OLs, the soma [Ca2+]i was never high when process [Ca2+]i was high. All data are mean±SEM.

Supplementary Figure 2 Dependence of sheath elongation on [Ca2+]i properties

(a-c) Change of sheath length (in 68 sheaths from 6 animals) correlates significantly with sheath [Ca2+]i transient (a) duration, (b) amplitude and (c) area (ʃ[ΔF/F] dt). (d) Change of sheath length does not correlate significantly with soma [Ca2+]i transient rate (in 54 sheath-soma pairs from 6 animals). (e) Increase of sheath length and [Ca2+]i transient rate in 14 lengthening sheaths which were of constant length for at least 1 hour before lengthening started, with data aligned at t=0 at the start of growth. [Ca2+]i transients precede sheath growth by ~1 hour. Data are mean±SEM.

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Krasnow, A.M., Ford, M.C., Valdivia, L.E. et al. Regulation of developing myelin sheath elongation by oligodendrocyte calcium transients in vivo. Nat Neurosci 21, 24–28 (2018). https://doi.org/10.1038/s41593-017-0031-y

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