Developmental loss of oligodendrocytes hinders adult CNS remyelination and increases astroglial and microglial activation

Abstract

Multiple sclerosis, a neurodegenerative autoimmune disease characterized by loss of oligodendrocytes and myelin in the brain and spinal cord, results in localized functional deficits. Several risk factors have been associated with MS, however none can fully explain enhanced susceptibility to MS. Epidemiological data, based on geographical prevalence studies suggest susceptibility is established early in life and frequently long before disease diagnosis indicating developmental events influence adult disease progression. Here we test the hypothesis that loss of mature oligodendrocytes during postnatal development results in enhanced susceptibility to a second demyelinating insult. A transgenic mouse model was utilized to specifically induce apoptosis in a subset of mature oligodendrocytes (MBP‐iCP9) during the first 2 postnatal weeks followed by either a local LPC spinal cord injection or the induction of EAE in the adult. Immunostaining, immunoblotting, behavioral testing, and scanning electron microscopy were utilized to examine the differences between groups. We show that during development, oligodendrocyte apoptosis results in transient reductions in myelination and functional deficits that recover after 10–14 days. Compared to animals in which oligodendrocyte development was unperturbed, animals subjected to postnatal oligodendrocyte ablation showed delayed recovery from an LPC lesion. Unexpectedly, the induction and severity of EAE was not significantly altered in animals following oligodendrocyte ablation even though there was a substantial increase in spinal cord tissue damage and CNS inflammation. It is currently unclear why these changes are not reflected in enhanced functional deficits. These observations suggest that developmental loss of oligodendrocytes results in long lasting tissue changes that alter its capacity for repair in the adult.Support or Funding InformationNIH834857