Final Report Summary - AXOGLIA (The role of myelinating glia in preserving axon function) AxoGLIA comprises a conceptually novel line of research that analyses the unknown mechanisms that initiate CNS myelination and mediate the long-term interactions of axons and oligodendrocytes, which are more complex than a simple membrane ensheathment for rapid impulse propagation. By generating several mouse mutants, we could demonstrate that a single developmental switch in neurons, an elevation of Akt/mTOR signalling, can induce the entire program of oligodendrocyte precursor recruitment, differentiation and myelination. It triggers the upregulation of a plethora of soluble factors, some of which we could analyse in considerable detail. Our data suggest that when looking for therapeutic targets of myelin repair also neuronal signalling mechanisms should be considered. In a parallel line of AxoGLIA research we found that axons and oligodendrocytes are metabolically coupled. Unexpectedly, once myelination is completed in postnatal development the mature oligodendrocytes live largely by aerobic glycolysis and deliver excess lactate/pyruvate to the axonal compartment, where ATP is generated to sustain axon functions. This solves the theoretical problem that axons are shielded from rapid access to extracellular glucose by myelin itself. Our model of oligodendrocyte function could become a paradigm shift for the role of myelinating glial cells in the nervous system, with implications for demyelinating, such as multiple sclerosis, and neurodegenerative diseases. We could also show that neuronal electrical activity, known to cause release of glutamate also along the axon, activates glucose transporters in oligodendrocytes and the myelin compartment following an activation of oligodendroglial NMDA-type glutamate receptors. This mechanism is ideally suited to roughly match the extent of oligodendroglial glycolytic support to the real underlying energy needs, and to prevent an excess release of lactate that would cause damage by acidification. Results of AxoGLIA research have been disseminated in leading scientific journals, such as Nature, Nature Neuroscience and Neuron.
