The voltage‐gated calcium channel CaV1.2 promotes adult oligodendrocyte progenitor cell survival in the mouse corpus callosum but not motor cortex

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.

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Is a Negative Regulator of Oligodendrocyte Progenitor Cell Differentiation in the Adult Mouse Brain

“…Please note that two distinct Pdgfrα-CreER transgenic mouse lines were used in this study: the Pdgfrα-CreER TM transgenic mouse line (Kang et al, 2010) was used for the majority of experiments and the lower efficiency (LE) Pdgfrα-CreER T 2 transgenic mouse line (Rivers et al, 2008), was used to perform the Tau-mGFP lineage tracing experiments, as we have previously demonstrated that the Pdgfrα-CreER TM transgenic mouse line cannot be used to induce OPC-specific recombination of the Tau-mGFP reporter, despite achieving the OPC-specific recombination of other transgenes (Pitman et al, 2019).…”

“…Acute coronal brain slices (300 µm) were generated from adult mice carrying the Pdgfrα-histGFP transgene using a VT1200s vibratome (Leica) as previously described (Pitman et al, 2019). Brain slices were transferred to a bath constantly perfused (2 ml/min) with ∼21 • C artificial cerebral spinal fluid (ASCF) containing: 119 mM NaCl, 1.6 mM KCl, 1 mM NaH 2 PO 4 , 26.2 mM NaHCO 3 , 1.4 mM MgCl 2 , 2.4 mM CaCl 2 , and 11 mM glucose (300 ± 5 mOsm/kg), saturated with 95% O 2 /5% CO 2, Whole cell patch clamp recordings of GFP + cells in the motor cortex were collected using a HEKA Patch Clamp EPC800 amplifier and pCLAMP 10.5 software (Molecular devices; RRID: SCR_011323).…”

“…Voltage gated calcium channel (VGCC) current recordings were made using solutions previously described (Pitman et al, 2019). All other voltage gated currents (potassium and sodium) were blocked.…”

“…As OPC physiology changes considerably between development and adulthood, and can also differ between CNS regions (Velez-Fort et al, 2010;Pitman et al, 2019;Spitzer et al, 2019), we examined the importance of LRP1 for adult OPC function. The conditional deletion of Lrp1 from adult OPCs (Pdgfrα-CreER :: Lrp1 fl/fl ) revealed that LRP1 is a negative regulator of oligodendrogenesis in the healthy adult mouse brain.…”

Strategies for Neuroprotection in Multiple Sclerosis and the Role of Calcium

“…Their main purpose is the formation of the myelin sheath [4,5], which is complex and requires different stimuli. The influx of calcium is important for the maturation of oligodendrocyte precursor cells (OPC) and the induction of myelination [6][7][8]. Additionally, the local calcium concentration seems to be essential for myelin elongation and sheath development [9][10][11].…”