High-efficiency pharmacogenetic ablation of oligodendrocyte progenitor cells in the adult mouse CNS

Abstract

Summary: Approaches to investigate adult oligodendrocyte progenitor cells (OPCs) by targeted cell ablation in the rodent CNS have limitations in the extent and duration of OPC depletion. We have developed a pharmacogenetic approach for conditional OPC ablation, eliminating >98% of OPCs throughout the brain. By combining recombinase-based transgenic and viral strategies for targeting OPCs and ventricular-subventricular zone (V-SVZ)-derived neural precursor cells (NPCs), we found that new PDGFRA-expressing cells born in the V-SVZ repopulated the OPC-deficient brain starting 12 days after OPC ablation. Our data reveal that OPC depletion induces V-SVZ-derived NPCs to generate vast numbers of PDGFRA+NG2+ cells with the capacity to proliferate and migrate extensively throughout the dorsal anterior forebrain. Further application of this approach to ablate OPCs will advance knowledge of the function of both OPCs and oligodendrogenic NPCs in health and disease. Motivation: To investigate the function of oligodendrocyte progenitor cells (OPCs), several groups have developed strategies to deplete OPCs within the adult CNS. However, these methods have significant limitations in achieving complete or long-term OPC ablation. We developed a pharmacogenetic method that achieves near-complete ablation of OPCs via the inducible and conditional expression of diphtheria toxin A (DTA) in adult OPCs followed by delivery of an anti-mitotic agent into the CNS to ablate dividing OPCs that escape genetic targeting.

Keywords

• CP: neuroscience