Oligodendroglial Interactions Group

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

The capacity for oligodendrocytes to effect a change in brain function is explained by the dramatic increase in impulse propagation speed and efficiency that occurs when axons are myelinated. Critically, in most white matter tracts, myelination is selective, only appearing in a subpopulation of axons, and the precise structure of individual myelin internodes has a marked influence over action potential propagation. Yet the mechanisms that regulate which axons or axonal domains become myelinated and the functional connectivity between neurons and oligodendrocytes is poorly understood. Beyond ligand/receptor-mediated interactions, neuronal activity is an essential factor that dictates which axons become myelinated. The release of ATP from excited axons stimulates the differentiation of oligodendrocyte progenitor cells (OPCs) directly via purinergic receptors and indirectly by stimulating astrocytes to release the cytokine leukemia inhibitory factor, which promotes OPC differentiation. In addition, unmyelinated axons form synapses with OPCs, and vesicular release of the neurotransmitter glutamate binds AMPA receptors on OPCs to stimulate myelination. Blocking electrical activity during developmental myelination impairs the proliferation of OPCs and the final stages of oligodendrocyte differentiation. Further, studies in Dr. Mersons group and others have demonstrated that increasing the activity of subsets of axons results in their selective myelination, and conversely, decreasing their activity reduces their myelination. These data indicate that activity-dependent myelination of axons likely plays a vital role in defining the repertoire of myelinated and unmyelinated axons generated developmentally and during ongoing plasticity. However, we still need to understand how populations of axons that require synchronous activity are myelinated to a similar extent to ensure that signals are received at their post-synaptic targets with appropriate isochronicity. The Oligodendroglial Interactions Group is developing approaches to link structural relationships between neurons and glia to functional outcomes in terms of the function of specific neural networks. The research approach leans heavily on using existing and novel transgenic tools to manipulate and record the functional interplay between oligodendroglia and axonal targets. We are developing the capability to assess the extent to which oligodendrocytes communicate with one another in executing myelination of a standard set of axons. We are utilizing these resources to test that activity-dependent changes in myelin morphology tune axonal properties via persistent bidirectional signaling between oligodendrocytes and their target axons. Another critical area of interest for the Merson Group is the cellular and molecular mechanisms orchestrating myelin repair after a demyelinating injury. Demyelination is a common pathological consequence of several neurodegenerative and neurological conditions, including multiple sclerosis, a disease that carries a significant psychological toll. We have previously demonstrated that in addition to OPCs, neural precursor cells (NPCs) that derive from the ventricular-subventricular zone (V-SVZ) also contribute to remyelination following cuprizone-mediated demyelination of the corpus callosum in mice. We have been interested in developing approaches to probe the relative importance of OPCs and NPCs to the regenerative process, given that these two populations of progenitor cells regenerate myelin that exhibits vital structural differences. Specifically, we revealed that while OPCs regenerate thin myelin sheaths during remyelination, NPCs regenerate significantly thicker myelin and more akin to normal healthy myelin. To explore the functional differences between myelin regenerated from oligodendrogenesis cells of NPC versus OPC origin, we have been developing tools to genetically ablate OPCs from the adult CNS so that we can examine remyelination mediated by NPCs in the absence of OPCs. Approaches to ablate OPCs in the rodent CNS have been limited in the extent and duration of OPC depletion. In recently published work from the group (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10014347/), we demonstrate the development of 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 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.