Axon Conduction and Survival in CNS White Matter During Energy Deprivation: A Developmental Study

Abstract

We investigated the postnatal development of axon sensitivity to the withdrawal of oxygen, glucose, or the combined withdrawal of oxygen + glucose in the isolated rat optic nerve (a CNS white matter tract). Removal of either oxygen or glucose for 60 min resulted in irreversible injury in optic nerves from adult rats, assessed by loss of the evoked compound action potential (CAP). Optic nerves at ages <P10 showed no permanent loss of function. CAP sensitivity to the withdrawal of oxygen or glucose emerged during a critical period in development between postnatal days 10-20 (P10-P20). The CAP was unchanged in adult optic nerve for 45 min after the withdrawal of glucose, demonstrating the presence of a significant energy reserve. Periods of glucose withdrawal >45 min caused the selective loss of late CAP components; this was not seen with oxygen deprivation. The amplitude of the early component recovered to 94.8% of control after 60 min of glucose withdrawal, although total CAP area recovered to only 42.3%. Combined oxygen + glucose withdrawal for 60 min produced a greater degree of permanent CAP loss than 60 min of glucose or oxygen withdrawal individually in optic nerves from rats older than P4. Younger than P4 optic nerves showed no permanent loss of function from 60 min of combined oxygen + glucose withdrawal. Unexpectedly, optic nerves from P21-P49 rats recovered significantly less after all three conditions than adult opticnerves (>P50). It is probable that this period of final myelination corresponds to a time of heightened metabolic activity in white matter. The tolerance of CNS white matter to energy deprivation can be categorized into four stages that are correlated with specific developmental features: premyelination (P0-P4), highly tolerant to anoxia, aglycemia and combined anoxia/aglycemia; early myelination (P5-P20), partially tolerant of anoxia and aglycemia but not to combined anoxia/aglycemia; late myelination (P21-P49), very low tolerance of anoxia, aglycemia and combined anoxia/aglycemia; and mature (>P50), low tolerance of anoxia, aglycemia and combined anoxia/aglycemia. The relative resistance of optic nerve function to glucose withdrawal in the presence of oxygen, compared with glucose withdrawal in the absence of oxygen, is presumably due to the presence of oxygen-dependent energy reserves such as astrocytic glycogen, amino acids. and phospholipids.

Conduction block and glial injury induced in developing central white matter by glycine, GABA, noradrenalin, or nicotine, studied in isolated neonatal rat optic nerve

“…As previously reported (Fern et al, 1998), compound action potential recordings from P10 rat optic nerve were stable during control perfusion with aCSF (10 µM added as above), only served to increase the rate of action potential decline produced by noradrenalin (Fig 3 B). This curious result may be explained by the direct actions of adrenoreceptor blockers upon the compound action potential.…”

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

“…An advantage of this preparation is that function can be monitored continuously. Optic nerve function persists for ϳ30 min in the absence of glucose (Ransom and Fern, 1997;Fern et al, 1998), suggesting the presence of an intrinsic energy reserve such as astrocytic glycogen. It also is known that the optic nerve, like other neural tissues, can survive on substrates other than glucose, making it feasible that a breakdown product of glycogen other than glucose could mediate the energy transfer between astrocytes and axons (Schurr et al, 1988;Larrabee, 1995;Ransom and Fern, 1997).…”

Functions of optic nerve glia: axoglial signalling in physiology and pathology

“…Removal of glucose, such as that which might occur when blood supply is compromised, results in an irreversible loss of optic nerve function, but astrocyte glycogen can support axonal function in the absence of glucose. [60][61][62][63] Glycogen is the single largest energy reserve in the brain and is localised entirely in astrocytes, which break it down to lactate, for transfer to axons. [60][61][62][63] Glycogen turnover is rapid and coordinated with optic nerve activity, 63 possibly via the activitydependent increase in [K þ ] o or glutamate, which are directly related to axonal activity (Figure 3g), 55 and mediate a Ca 2 þ -dependent glycogen breakdown.…”