Metabolic aspects of neuron-oligodendrocyte-astrocyte interactions

Abstract

Whereas astrocytes have been in the limelight of scientific interest in brain energy metabolism for a while, oligodendrocytes are still waiting for a place on the metabolic stage. We propose to term the interaction of oligodendrocytes with astrocytes and neurons: NOA (neuron-oligodendrocyte-astrocyte) interactions. One of the reasons to find out more about metabolic interactions between oligodendrocytes, neurons, and astrocytes is to establish markers of healthy oligodendrocyte metabolism that could be used for the diagnosis and assessment of white matter disease. The vesicular release of glutamate in the white matter has received considerable attention in the past. Oligodendrocyte lineage cells express glutamate receptors and glutamate toxicity has been implicated in diseases affecting oligodendrocytes such as hypoxic-ischaemic encephalopathy, inflammatory diseases and trauma. As oligodendrocyte precursor cells vividly react to injury it is also important to establish whether cells recruited into damaged areas are able to regenerate lost myelin sheaths or whether astrocytic scarring occurs. It is therefore important to consider metabolic aspects of astrocytes and oligodendrocytes separately. The present review summarizes the limited evidence available on metabolic cycles in oligodendrocytes and so hopes to stimulate further research interests in this important field.

Keywords: energy metabolism; glucose; glycolysis; gray matter; lactate; monocarboxylate transporters; pyruvate carboxylation; white matter.

Figure 1

Schematic overview of the metabolic interactions between neurons–oligodendrocytes–astrocytes (NOA) discussed in this review. Glucose (GLC) from the blood is taken up by neurons, astrocytes, and oligodendrocytes and can be metabolized via glycolysis, giving rise to pyruvate (PYR). In astrocytes, GLC can also be stored in the form of glycogen. PYR, the end product of glycolysis can be reduced to lactate (LAC) which can be released and taken up by cells with lower lactate concentration, be converted into alanine (not shown) or be converted into acetyl-CoA (Ac-CoA) and subsequently oxidized in the tricarboxylic acid (TCA) cycle. After synaptic release of glutamate (GLU) by neurons, astrocytes are responsible for most of its uptake via specific high-affinity glutamate transporters to prevent neuronal excitotoxicity, although some pre-synaptic re-uptake can also occur. GLU taken up by astrocytes can be converted to glutamine (GLN) by glutamine synthetase (GS) which can be transferred to neurons where it is transformed into GLU, making it available again for neurotransmission and, in this way, closing the GLU-GLN cycle. The close association between GLU, GLN, and TCA cycle metabolism is indicated in the three cell compartments: GLU can be additionally converted into α-ketoglutarate (α-KG) and be subsequently oxidized. Even though there are reports on the absence of glutamine synthetase and pyruvate carboxylase (PC) in oligodendrocytes, it is not totally clear whether or not they are capable of synthesizing GLN and performing anaplerosis. Finally, neurons are known to synthesize N-acetyl-aspartate (NAA) from aspartate (ASP) and Ac-CoA. NAA is thought to be transferred to oligodendrocytes where it is metabolized into ASP and acetate. Whereas the resulting acetate is thought to be extensively used for the synthesis of myelin lipids, the fate of the ASP is still unresolved since it can either be metabolized in oligodendrocytes or transported back to neurons, closing another potentially important metabolic cycle in the brain.