Biomedical subjects

Selva Baltan Tekkök

Publications and source records attributed to Selva Baltan Tekkök.

6 recordsLinked to original sources

PubMed2005

Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity.

It is hypothesized that L-lactate derived from astrocyte glycogen sustains axon excitability in mouse optic nerve (MON). This theory was tested by using a competitive antagonist of L-lactate transport and immunocytochemistry to determine whether transport proteins are appropriately distributed in adult MON. L-lactate sustained the compound action potential (CAP), indicating that exogenous L-lactate was an effective energy substrate. During 60 min of aglycemia, the CAP persisted for 30 min, surviving on a glycogen-derived substrate (probably lactate), before failing. After failing, the CAP could be partially rescued by restoring 10 mM glucose or 20 mM L-lactate. Aglycemia in the presence of 20 mM D-lactate, a metabolically inert but transportable monocarboxylate, resulted in accelerated CAP decline compared with aglycemia alone, suggesting that D-lactate blocked the axonal uptake of glycogen-derived L-lactate, speeding the onset of energy failure and loss of the CAP. The CAP was maintained for up to 2 hr when exposed to 20% of normal bath glucose (i.e., 2 mM). To test whether glycogen-derived L-lactate "supplemented" available glucose (2 mM) in supporting metabolism, L-lactate uptake into axons was reduced by the competitive inhibitor D-lactate. Indeed, in the presence of 20 mM D-lactate, the CAP was lost more rapidly in MONs bathed in 2 mM glucose artificial cerebrospinal fluid. Immunocytochemical staining demonstrated cell-specific expression of monocarboxylate transporter (MCT) subtypes, localizing MCT2 predominantly to axons and MCT1 predominantly to astrocytes, supporting the idea that L-lactate is released from astrocytes and taken up by axons as an energy source for sustaining axon excitability.

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PubMed2005

AMPA/kainate receptors mediate axonal morphological disruption in hypoxic white matter.

We used acute brain slices to investigate the hypothesis that oxygen-glucose deprivation (OGD) induced loss of axon function and neurofilament labeling are correlated to axonal morphological disruption in the corpus callosum of adult brain. Coronal brain slices including corpus callosum were prepared from adult mice. White matter immunohistochemical properties and conduction along axons remained stable over 12 h after preparation. White matter injury was assessed by recording compound action potentials (CAPs) across corpus callosum, combined with immunofluorescence for axonal neurofilaments and by bright field microscopy of myelin profiles in semi-thin sections. OGD for 30 min resulted in irreversible loss of the CAPs, formation of axon heads and bulbs, and swelling of myelin profiles in slices examined 1h after OGD. In slices followed for 9 h after OGD, there was complete loss of neurofilament labeling and myelin profiles. Because overactivation of AMPA/kainate receptors mediates axon structural and functional disruption in hypoxic corpus callosum slices, we tested whether blockade of AMPA/kainate receptors reduced OGD-induced axonal morphological disruption. NBQX (30 microM), an AMPA/kainate receptor antagonist, prevented OGD-induced formation of axon heads and bulbs, swelling of myelin profiles, loss of neurofilament staining and preserved axonal morphology. These results expand our previous findings that the AMPA/kainate receptor activation contributes to axonal morphological disruption, as well as loss of electrical function.

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PubMed2004

Anoxia effects on CNS function and survival: regional differences.

The effects of anoxia on function and survival of different central nervous system (CNS) areas were tested. As expected, synaptic function in a typical gray matter area of the brain, hippocampus, failed rapidly during 30 min of anoxia and did not recover. Mouse optic nerve and corpus callosum, two white matter (WM) areas of the brain, showed persistent function during total anoxia for periods as long as two hours. Moreover, even after two hours of anoxia followed by a recovery period, nearly half of the axons that were excitable at the outset remained functional. The corpus callosum contains a high percentage of unmyelinated axons while optic nerve axons are completely myelinated. These studies indicate that CNS structures vary greatly in their ability to function and survive anoxia. Mammalian WM, independent of myelination, is remarkably tolerant of anoxia implying that CNS axons generate enough ATP by anaerobic energy metabolism to sustain function.

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PubMed2004

Energy transfer from astrocytes to axons: the role of CNS glycogen.

We tested the hypothesis that astrocytic glycogen supports axon function under both pathological and physiological conditions. Functional activity of the rat (RON) or mouse optic nerve (MON), representative central white matter tracts, was assessed electrophysiologically as the area under the supramaximal compound action potential (CAP). During aglycaemia the CAP area of rodent optic nerve persisted for up to 30 min, after which the CAP rapidly failed. Glycogen content measured biochemically during the aglycaemic insult fell with a time course compatible with its rapid degradation in the absence of glucose. Pharmacological up-regulation of glycogen content prior to the aglycaemic insult with incubation in hyperglycaemic ambient glucose delayed CAP failure, whereas down-regulation of glycogen content induced by nor-adrenaline accelerated CAP failure. Inhibiting lactate transfer between astrocytes and axons during aglycaemia, where glycogen is the only utilisable energy reserve, resulted in accelerated CAP failure, implying that glycogen-derived lactate supports function when exogenous energy metabolites are withdrawn. Under normoglycaemic conditions glycogen content decreased during high frequency axon discharge, although CAP function was fully maintained. Both prior depletion of glycogen content, or blocking axonal lactate uptake rendered nerves incapable of fully supporting CAP function during high frequency firing in the presence of normoglycaemic glucose. These results indicated that during aglycaemia and increased metabolic demand, astrocytic glycogen was degraded to form lactate, which was used as a supplemental energy source when ambient normoglycaemic glucose was incapable of meeting immediate tissue energy demands.

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PubMed2003

Glycogen regulation and functional role in mouse white matter.

CNS glycogen, contained predominantly in astrocytes, can be converted to a monocarboxylate and transported to axons as an energy source during aglycaemia. We analysed glycogen regulation and the role of glycogen in supporting neural activity in adult mouse optic nerve, a favourable white matter preparation. Axon function was quantified by measuring the compound action potential (CAP) area. During aglycaemia, axon function persisted for 20 min, then declined in conjunction with glycogen content. Lactate fully supported CAPs in the absence of glucose, but was unable to sustain glycogen content; thus, axon failure occurred rapidly when lactate was withdrawn. Glycogen content in the steady state was directly proportional to bath glucose concentration. Increasing [K+]o to 10 mM caused a rapid decrease in glycogen content. Latency to onset of CAP failure during aglycaemia was directly proportional to glycogen content and varied from about 2 to 30 min. Intense neural activity reduced glycogen content in the presence of 10 mM bath glucose and CAP area gradually declined. CAP area declined more rapidly during high frequency stimulation if monocarboxylate transport was inhibited. This suggested that astrocytic glycogen was broken down to a monocarboxylate(s) that was used by rapidly discharging axons. Likewise, depleting glycogen by brief periods of high frequency axon stimulation accelerated onset of CAP decline during aglycaemia. In summary, these experiments indicated that glycogen content was under dynamic control and that glycogen was used to support the energy needs of CNS axons during both physiological as well as pathological processes.

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PubMed2003

Axon function persists during anoxia in mammalian white matter.

Axon function in the CNS has been reported to fail rapidly during anoxia, implying that there is no anaerobic capacity. This phenomenon was reassessed in rodent white matter using mouse or rat optic nerve. Axon function was semiquantitatively measured as area under the compound action potential. Mouse optic nerves exposed to anoxia (30-180 minutes) or cyanide (30-60 minutes) at 37 degrees C exhibited significant persistent function that was abolished by removing glucose. Reduction in compound action potential area increased with anoxia duration reaching a maximum of about 70% after 90 min. Rat optic nerves exposed to anoxia, in contrast to mouse optic nerves, showed rapid and complete loss of function. When artificial CSF glucose was increased from 10 to 30 mmol/L, rat optic nerves responded to anoxia in a similar manner to mouse optic nerves in 10-mmol/L glucose. The authors conclude that white matter is resistant to anoxia with a subset of axons able to subsist exclusively on anaerobically derived energy. Because the rat optic nerve is about twice the diameter of the mouse optic nerve, glucose diffusion into the rat optic nerve was inadequate during anoxia when artificial CSF glucose was 10 mmol/L but became adequate when artificial CSF glucose was 30 mmol/L. These observations have implications for white matter energy metabolism and susceptibility to injury during focal ischemia.

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