Norepinephrine regulates Ca²⁺ signals and fate of oligodendrocyte progenitor cells in the cortex

Abstract

Oligodendrocyte precursor cells (OPCs) represent the most abundant group of proliferating cells in the adult central nervous system. OPCs serve as progenitors for oligodendrocyte (OLs) throughout the life, and contribute to developmental and adaptive myelination, and myelin repair during diseased state. OPCs make synaptic and extra-synaptic contacts with axons, and detect and respond to neuronal activity. How OPCs translate the information relayed by the neuronal activity into Ca2+ signals, which in turn influence their fate and survival, is less understood. We developed novel transgenic mouse lines expressing a cytosolic and membrane anchored variants of genetically encoded Ca2+ sensors (GCaMP6f or mGCaMP6s) in OPCs, performed 2-photon microscopy in the somatosensory cortex of the awake behaving mice, and simultaneously monitored intracellular Ca2+ signals and their cell-fate progression. We found Ca2+ signals in OPCs mainly occur within processes and confine to micrometer-size segments called Ca2+ microdomains. Microdomain Ca2+ signals enhanced in OPCs when mice engage in exploratory behavior. OPCs exhibit distinct Ca2+ signals while they proliferate to maintain their precursor pool or differentiate to generate new OL. When mice engaged in exploratory behavior, the cortical projections of noradrenergic neurons in locus coeruleus showed increased firing rate and norepinephrine release. Norepinephrine activated all three subtypes of alpha1 adrenergic receptor expressed by OPCs and evoked intracellular Ca2+ increase in OPCs. A chemogenetic activation of noradrenergic neurons, promoted differentiation of cortical OPCs into OL, and at the same time suppressed OPC proliferation rate. Hence, we uncovered that various cell types of oligodendrocyte lineage exhibits unique signatures of Ca2+ activity, which these cells might integrate for making their fate decisions, and norepinephrine signaling can be a potent regulator of OPC fate.

Synapses and Ca2+activity in oligodendrocyte precursor cells can predict where myelin sheaths form

“…We found that 99% of Ca 2+ events in OPCs occurred in MDs on processes, and 97% of OPCs exhibited only MD Ca 2+ activity during our recordings (Fig. 6c, Supplemental Video 3-4), consistent with recent work in mammals 43,44 . We examined the proximity between Ca 2+ events in MDs and a presynaptic marker, synaptophysin-RFP 17 .…”

“…For example, some OPCs exhibit no change or even an increase of Ca 2+ activity upon TeNT treatment or TTX treatment while most OPCs exhibit reduction. These “outlier” OPCs and activity could be due to Ca 2+ generated from synapse-independent mechanisms, such as adrenergic receptor-mediated Ca 2+ activity as recently suggested in cerebral cortex 43,44 . In line with this, nearly 61% of Ca 2+ MDs do not associate with presynaptic markers, and nearly 55% residual Ca 2+ activity remains after TeNT treatment, supporting synapse-independent Ca 2+ - inducing mechanisms in OPCs as well as synapse-dependent mechanisms.…”

“…(e) Average myelin sheath length in (d). n = 24 and 22 cells from 15 fish; t [44] = 2.247. All data are represented as mean ± SEM; N.S., not significant; (e) unpaired t-test; scale bars 5 μm.…”

“…Several studies have identified synaptic mechanisms underlying Ca 2+ elevation in OPCs under conditions of increased neuronal activity (e.g., through axon stimulation) with a focus on somal activity [14][15][16]54 . Interestingly, recent studies provided evidence that neuronal activity or synaptic release contribute little to OPC MD Ca 2+ activity in adult mice brains 43,44 . Like these studies, we find that OPC Ca 2+ activity in vivo mainly occurs in MDs; in contrast, we show that MD Ca 2+ activity does require synaptic release in the zebrafish spinal cord, suggesting interesting regional and/or developmental differences that will be important for future study.…”

Mitochondrial network reorganization and transient expansion during oligodendrocyte generation

“…Thus, arousal-dependent changes in mitochondria motility is consistent with recent evidence of decreased calcium dynamics in OPCs in anesthesia conditions or when norepinephrine release is blocked 63 . Norepinephrine can influence the differentiation and/or proliferation of oligodendrocytes and the expression of norepinephrine receptors in the OPCs changes with their differentiation 63,64,67 . Overall, these observations suggest a potential connection between mitochondria and calcium dynamics and raise questions for how animal arousal state influences mitochondria in these cells and therefore the cell fate in the oligodendrocyte lineage.…”