Genetic Evidence For Neuron-Glia Metabolic Coupling In The CNS

The active contribution of oligodendrocytes and astrocytes to sustain brain physiology was completely underestimated, but severe consequences of their dysfunction in various diseases and glia-specific mutants emphasized their importance in maintaining neuronal integrity and function. By the intimate interconnection between neurons, oligodendrocytes and astrocytes a network is established allowing bidirectional interaction. Improved techniques to analyze brain energy metabolism revealed that a high amount of glucose is not oxidatively metabolized. Thus, lactate, the end-product of aerobic glycolysis, is accepted to play an important role in fueling the brain. In this context, oligodendrocytes and astrocytes were assumed to produce lactate that is shuttled to neuronal compartments to benefit mitochondrial respiration and local energy requirements. To obtain supportive evidence for this hypothesis, conditional mouse mutants were generated by targeting COX10, essential to assemble COX (cytochrome c oxidase), the terminal complex of the mitochondrial respiratory chain. Consequently, Cox10-deficient cells can only survive by aerobic glycolysis or die. By using well-established Cre-driver mouse lines, selective recombination was achieved in oligodendrocytes and mature Bergmann glia, a cerebellar subpopulation of astrocytes, respectively. In both, disrupted oxidative phosphorylation did not affect the survival of Cox10ablated cells. In the CNS, neurodegeneration, secondary inflammation or abnormal regeneration were not detected in both conditional mutants. Furthermore, the absence of oligodendroglial myelin defects and the normal appearance of synapses engulfed by Bergmann glia, respectively, reflect the ease of adaptation to aerobic glycolysis of these cells. Importantly, elevated lactate concentrations were detected in the living brain of oligodendroglial mutant and control mice by in vivo magnetic resonance spectroscopy. This was only reached when mice were exposed to isoflurane anaesthesia which blocks the pyruvate dehydrogenase complex. Furthermore, lactate accumulations immediately dropped by the end of anaesthesia to undetectable levels suggesting a model in which aerobic glycolysis products from oligodendrocytes are rapidly metabolized within white matter tracts in the healthy brain. To investigate a possible underlying mechanism, PKM2 expression was analyzed. This is an isozyme of the pyruvate kinase, specifically upregulated in cancers and highly proliferating cells. The shift of PKM1 to PKM2 is debated to promote aerobic glycolysis in cancer cells and thus tumor growth and proliferation. In adult wildtype mouse brains PKM2 was expressed in cells with oligodendrocyte-like morphology and protein analysis displayed high PKM2 expression abundance in white matter tracts. A possible regulatory mechanism controlling PKM2 activity and thus the velocity of glycolysis was unraveled by the detection of phosphorylated PKM2 in different adult brain regions. Taken together, these findings implicate specific metabolic properties of oligodendrocytes and astrocytes enabling a metabolic coupling to neurons that serves a physiological function.