Conditional deletion of L-type calcium channels in oligodendrocyte progenitor cells affects remyelination in mice

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Demyelination impairs axon conduction and can lead to deficits in motor, sensory and/or cognitive function depending on the location of the affected axons. Remyelination occurs in many MS lesions, but becomes increasingly less effective over time and eventually fails. Our findings indicate a role for L-type voltage-operated calcium channels (L-VOCCs) as potential modulators of oligodendrocyte progenitor cell (OPC) development in the postnatal mouse brain. To determine whether L-VOCCs are required for OPC development and remyelination, we have generated an inducible conditional knockout mouse in which the L-VOCC isoform Cav1.2 was deleted in NG2 positive OPCs. Using the cuprizone model of demyelination we establish that Cav1.2 deletion in OPCs lead to less efficient remyelination of the adult brain. We have found that Cav1.2 deficient OPCs are less effective in remyelinating several structures of the adult brain including the corpus callosum and cortex. Specifically, Cav1.2 KO OPCs mature slower and produce less myelin than control oligodendrocytes after two and four weeks of recovery following the cuprizone intoxication. Furthermore, during the recovery period of the cuprizone model the corpus callosum of Cav1.2 KO animals presented an important decrease in the percentage of myelinated axons and a substantial increase in the mean g-ratio of myelinated axons compare to controls. These results suggest that Ca⁺⁺ influx mediated by L-VOCCs in oligodendroglial progenitor cells is necessary for normal remyelination and is an essential calcium channel for OPC maturation during the remyelination process.

Support or Funding Information

NIH/NINDS grant 1R01NS078041-03A1 and National Multiple Sclerosis Society Grant RG4554-A-2.