Abstract
Throughout life, oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes. OPCs express cell surface receptors and channels that allow them to detect and respond to neuronal activity, including voltage‐gated calcium channel (VGCC)s. The major L‐type VGCC expressed by developmental OPCs, CaV1.2, regulates their differentiation. However, it is unclear whether CaV1.2 similarly influences OPC behavior in the healthy adult central nervous system (CNS). To examine the role of CaV1.2 in adulthood, we conditionally deleted this channel from OPCs by administering tamoxifen to P60 Cacna1c fl/fl (control) and Pdgfrα‐CreER:: Cacna1c fl/fl (CaV1.2‐deleted) mice. Whole cell patch clamp analysis revealed that CaV1.2 deletion reduced L‐type voltage‐gated calcium entry into adult OPCs by ~60%, confirming that it remains the major L‐type VGCC expressed by OPCs in adulthood. The conditional deletion of CaV1.2 from adult OPCs significantly increased their proliferation but did not affect the number of new oligodendrocytes produced or influence the length or number of internodes they elaborated. Unexpectedly, CaV1.2 deletion resulted in the dramatic loss of OPCs from the corpus callosum, such that 7 days after tamoxifen administration CaV1.2‐deleted mice had an OPC density ~42% that of control mice. OPC density recovered within 2 weeks of CaV1.2 deletion, as the lost OPCs were replaced by surviving CaV1.2‐deleted OPCs. As OPC density was not affected in the motor cortex or spinal cord, we conclude that calcium entry through CaV1.2 is a critical survival signal for a subpopulation of callosal OPCs but not for all OPCs in the mature CNS.
Highlights
Oligodendrocyte progenitor cells (OPCs) are immature, proliferative cells that differentiate into mature, myelinating oligodendrocytes in the central nervous system (CNS)
While OPC proliferation was reduced in the corpus callosum, and brain slice culture experiments suggested that CaV1.2 was required for OPC migration, the hypomyelination was largely attributed to the impaired ability of OPCs to generate myelinating oligodendrocytes (Cheli et al, 2016)
To determine whether CaV1.2 could influence the maturation of adult-born oligodendrocytes, as reported in development (Cheli et al, 2016), we examined the morphology of individual myelinating oligodendrocytes in the motor cortex (Figure 3e,f,i,j) and corpus callosum (Figure 3o,p,s,t) of P60 + 30 control and CaV1.2-deleted mice
Summary
Oligodendrocyte progenitor cells (OPCs) are immature, proliferative cells that differentiate into mature, myelinating oligodendrocytes in the central nervous system (CNS). While OPC proliferation was reduced in the corpus callosum, and brain slice culture experiments suggested that CaV1.2 was required for OPC migration, the hypomyelination was largely attributed to the impaired ability of OPCs to generate myelinating oligodendrocytes (Cheli et al, 2016). Consistent with this finding, the deletion of CaV1.2 from adult OPCs was reported to reduce their capacity to remyelinate the corpus callosum following cuprizone-induced demyelination (Santiago González et al, 2017), suggesting that CaV1.2 can, at least following an injury, regulate adult OPC function. These data indicate that CaV1.2 is an essential survival signal for a subset of adult OPCs in the corpus callosum
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