DECODING THE DIFFERENTIAL REGULATION OF OLIGODENDROCYTE PRECURSOR CELLS PROLIFERATION AND DIFFERENTIATION BY <EM >CACNA2D1</EM> BETWEEN DEVELOPMENT AND ADULTHOOD

Myelination is essential for rapidly transmitting electrical impulses along axons in the central nervous system (CNS). Oligodendrocytes, the exclusive myelinating cells in the CNS, are differentiated from oligodendrocyte precursor cells (OPCs). OPCs persist in the postnatal CNS and remain proliferative even during adulthood. OPCs express abundant voltage-gated calcium channels (VGCCs). These VGCCs are considered to play a critical role in determining the proliferation and differentiation potential of OPCs and thus mediating myelin development, adaptation and repair. Alpha2delta1 (A2d1) subunits, the auxiliary subunits of various VGCCs, increase the membrane expression of VGCCs and subsequent Ca2+ current density. Previous transcriptomic studies showed that OPCs highly express Cacna2d1, the gene encoding A2d1. This study aims to investigate how A2d1 subunits expressed in OPCs regulate the proliferation and differentiation of OPCs and the subsequent myelination. We created a tamoxifen-inducible conditional knockout line that specifically deletes Cacna2d1 in OPCs at target periods. When Cacna2d1 was deleted in early postnatal OPCs, we observed reduced OPC proliferation rate and a decrease in OPC density, supporting the role of VGCCs in promoting OPC proliferation and myelin formation. Surprisingly, when Cacna2d1 was deleted in adult OPCs, our data demonstrated an increase in mature oligodendrocyte density and myelin sheath thickness. These histological changes were also accompanied by enhanced impulse conduction from corpus callosum axons. Therefore, A2d1 subunits of VGCCs appear to have distinct regulatory roles for OPC proliferation and differentiation during myelin development and adulthood.