Calcium Influx Through AMPA Receptors Inhibits Oligodendrocyte Regeneration in the Injured Brain

Abstract

Calcium influx through ionotropic glutamate receptors expressed on non-excitable glia may regulate important cell events via subcellular signaling mechanisms. Oligodendrocytes and OPCs, two glial populations supporting CNS myelination and myelin repair, express AMPA receptors (AMPARs), but the role of AMPAR-mediated calcium signaling in these glia is unclear. Here, we developed a mouse genetic system enabling cell-specific overexpression of GluA2, the calcium-impermeable subunit, and blocked calcium influx through AMPARs in oligodendroglia. Surprisingly, blocking AMPAR-mediated calcium did not alter normal oligodendrogenesis or myelin integrity. However, in neonatal white matter injury, the same manipulation significantly promoted oligodendrocyte regeneration and OPC proliferation, while it did not protect oligodendrocytes from their initial loss. Moreover, GluA2 overexpression stimulated transcriptional activities linked to myelinogenesis, even without injury. These results suggest that AMPAR-calcium signaling suppresses oligodendrocyte regeneration, and that targeting this mechanism by GluA2 upregulation may benefit myelin repair in pathological events involving demyelination.