Metabolism of oligodendrocytes and its involvement in axo‐glia interaction

by Andrea Trevisiol
Doctoral thesis
Date of Examination:2018-02-26
Date of issue:2019-03-12
Advisor:Prof. Dr. Klaus-Armin Nave
Referee:Prof. Dr. Silvio Rizzoli
Referee:Prof. Dr. Swen Hülsmann
Persistent Address: http://dx.doi.org/10.53846/goediss-7324

 

 

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Abstract

English

In white matter, axonal energy homeostasis critically depends on glial support. Failure in glial-mediated delivery of metabolic substrates into the axonal compartment results in axonal energy deficit and may anticipate axonal degeneration observed in myelin disorders and several neurodegenerative diseases. In mice, transgenic expression of an ATP-sensor in neurons allowed us to visualize axonal energy content in acutely isolated optic nerves while simultaneously performing electrophysiological compound action potentials (CAP) recordings. The real-time monitoring of activity-dependent axonal ATP revealed a strong correlation between axonal energy fluctuations and nerve conduction. Importantly, upon pharmacological inhibition of endogenous lactate metabolism while under continuous glucose supply, ATP-CAP correlation was disrupted, suggesting that the axonal glycolysis products alone were insufficient to maintain axonal mitochondrial energy metabolism during spiking activity. To determine possible metabolic consequences of myelin defects we monitored ATP and CAP in Plp1-null optic nerves. Genetic ablation of Plp1, encoding a myelin membrane protein, serves as a model of spastic paraplegia type-2, where functional but structurally destabilized myelin sheaths lead to secondary axonal loss. We found that the energy metabolism of myelinated axons of Plp1-null optic nerves is perturbed long before the onset of clinical symptoms and major pathological changes. These observations motivated us to assess the metabolic properties of spinal cord fibres in vivo to allow long-term studies involving demyelination and remyelination models. The parallel monitoring of axonal ATP and CAP is a powerful tool to study white matter metabolism and metabolic support mechanisms under physiological conditions and in models of neurodegenerative disorders.
Keywords: White matter; ATP; axo-glia; metabolism; cAP; optic nerve; PLP1
 
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