Metabolic interactions between axons and Schwann cells of the mouse sciatic nerve

Rich, Laura (2022) Metabolic interactions between axons and Schwann cells of the mouse sciatic nerve. PhD thesis, University of Nottingham.

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Astrocytes of the central nervous system (CNS) provide glycogen derived lactate to axons when energy substrate availability is low and when axons have an increased energy demand. Signals, including glutamate and K+, released from axons communicate the need for metabolic support and trigger astrocyte lactate production. Whether similar metabolic interactions occur between axons and Schwann cells of the peripheral nervous system (PNS) is less well understood. The association of peripheral neuropathy with the metabolic disease diabetes makes the study of axon-Schwann cell metabolic interactions valuable. Myelinating Schwann cells possess glycogen and glycolytically metabolise this to lactate, which their associated axons, known as A fibres, benefit from as an energy substrate when glucose availability is reduced. The aim of this thesis was to use the mouse sciatic nerve to investigate the role of Schwann cells in providing lactate to A fibres during increased axonal activity and the ability of K+ to act as a metabolic signal. Fructose metabolism of the mouse sciatic nerve was also investigated.

Stimulus evoked compound action potential (CAP) electrophysiology was used to measure the conduction of, and lactate biosensors were used to record the lactate released from, the mouse sciatic nerve ex vivo. The method of stimulus evoked CAP electrophysiology was first adapted to record from paired, rather than single nerves, reducing the number of required animals whilst maintaining statistical power. Using this adapted method nerves were subjected to high frequency stimulation (HFS) to increase energy demand. A fibre conduction was maintained through increased glucose supply or Schwann cell derived lactate. The importance of Schwann cell lactate was evident by the loss and inability to maintain recovery of conduction when cinnamate (CIN), an inhibitor that prevents the shuttling of lactate from Schwann cells to axons, was present under normoglycaemic conditions. These findings prompted investigations into K+ as a trigger of Schwann cell lactate production. Increasing the concentration of extracellular K+ increased the concentration of extracellular lactate, a relationship which was logarithmic in response to global changes in K+ within the artificial cerebrospinal fluid (aCSF), but not in response to local changes in K+ as the result of increasing stimulus frequency. This suggests the Schwann cell membrane potential influences lactate production. When fructose is supplied to the ex vivo sciatic nerve preparation, Schwann cells provide lactate to A fibres, with these axons unable to directly benefit from fructose. Using fluorescent immunohistochemistry, the expression of the fructose specific transporter, GLUT5, and the fructose metabolism specific enzyme, fructokinase, was not found to parallel these electrophysiology findings. With fructokinase expressed exclusively by A fibres and GLUT5 expressed by A fibres and myelinating Schwann cells. These molecular findings might reflect a neuroprotective strategy in which Schwann cells convert excess glucose to fructose via the polyol pathway, a pathway upregulated during diabetes. This fructose may then be shuttled to A fibres for metabolism via fructokinase.

These findings further our understanding of the metabolic role of Schwann cells and provide insight into the potential signal that enables metabolic communication between axons and Schwann cells.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Brown, Angus
Chakrabarti, Lisa
Keywords: Schwann cells, Mouse sciatic nerve, Axons
Subjects: Q Science > QH Natural history. Biology > QH573 Cytology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 67267
Depositing User: Rich, Laura
Date Deposited: 31 Jul 2022 04:40
Last Modified: 31 Jul 2022 04:40

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