Fructose metabolism in the adult mouse optic nerve, a central white matter tract.

Our recent report that fructose supported the metabolism of some, but not all axons, in the adult mouse optic nerve prompted us to investigate in detail fructose metabolism in this tissue, a typical central white matter tract, as these data imply efficient fructose metabolism in the central nervous system (CNS). In artificial cerebrospinal fluid containing 10 mmol/L glucose or 20 mmol/L fructose, the stimulus-evoked compound action potential (CAP) recorded from the optic nerve consisted of three stable peaks. Replacing 10 mmol/L glucose with 10 mmol/L fructose, however, caused delayed loss of the 1st CAP peak (the 2nd and 3rd CAP peaks were unaffected). Glycogen-derived metabolic substrate(s) temporarily sustained the 1st CAP peak in 10 mmol/L fructose, as depletion of tissue glycogen by a prior period of aglycaemia or high-frequency CAP discharge rendered fructose incapable of supporting the 1st CAP peak. Enzyme assays showed the presence of both hexokinase and fructokinase (both of which can phosphorylate fructose) in the optic nerve. In contrast, only hexokinase was expressed in cerebral cortex. Hexokinase in optic nerve had low affinity and low capacity with fructose as substrate, whereas fructokinase displayed high affinity and high capacity for fructose. These findings suggest an explanation for the curious fact that the fast conducting axons comprising the 1st peak of the CAP are not supported in 10 mmol/L fructose medium; these axons probably do not express fructokinase, a requirement for efficient fructose metabolism.

Fructose supports energy metabolism of some, but not all, axons in adult mouse optic nerve.

We used transmission electron microscopy (TEM) and electrophysiological techniques to characterize the morphology and stimulus-evoked compound action potential (CAP), respectively, of the adult mouse optic nerve (MON). Electrophysiological recordings demonstrated an identical CAP profile for each MON. An initial peak, smallest in area and presumably composed of the fastest-conducting axons displayed the lowest threshold for activation as expected for large axons. The second peak, the largest, was presumably composed of axons of intermediate diameter and conduction velocity, and the third peak was composed of the slowest and presumably smallest axons. In 10 mM fructose, the first CAP peak area was reduced by 78%, but the second and third peaks were unaffected. Histological analysis revealed a cross-sectional area of 33,346 microm2, containing 24,068 axons per MON. All axons were myelinated and axon diameter ranged from 0.09 to 2.58 microm, although 80 +/- 6% of the axons were <0.75 microm in diameter and only 0.6 +/- 0.3% of the axons were >2 microm in diameter. After bathing in fructose for 2 h 94 +/- 2% of normal appearing axons were <0.75 microm in diameter and none were >1.5 microm-all of the larger axons being grossly abnormal in structure. We conclude that fructose is unable to support function of the larger axons contributing to the first CAP peak, thus enabling us to identify a distinct population of axons that contributes to that peak.