Glucose metabolism in cholinoceptive cortical ratbrain regions after basal forebrain cholinergic lesion

Abstract

To address the question whether the changes in cortical glucose metabolism observedin patients with Alzheimers disease are interrelated with, or consequences of, basal forebraincholinergic cell loss, an experimental approach was employed to produce cortical cholinergicdysfunction in rat brain by administration of the cholinergic immunotoxin 192IgG-saporin. [14C]d-glucose utilization in brain homogenates, d-glucose-displaceable [3H]cytochalasin B binding to glucose transporters (GLUT),Northern and Western analyses, as well as in vivo [14]2-deoxyglucoseautoradiography were used to quantify the regional glucose metabolism.Basal forebrain cholinergic lesion resulted in transient increases in glucose transporterbinding in cortical regions displaying reduced acetylcholinesterase activity, already detectableseven days after lesion with peak values around 30 days post lesion. Western analysis revealedthat the changes in total glucose transporter binding are mainly due to changes in the GLUT3subtype only, while the levels of GLUT1 and GLUT3 mRNA (Northern analysis) were notaffected by cholinergic lesion. Both immunocytochemistry and in situ hybridizationdemonstrated preferential localizations of GLUT1 on brain capillaries and GLUT3 on neurons,respectively. A lesion-induced transient decrease in [14C]d-glucoseutilization seven days post lesion was detected in the lesion site, whereas cholinoceptive corticalregions were not affected. In vivo [14C]deoxyglucose uptake was transientlyincreased in cholinoceptive cortical regions and in the lesion site being highest between three toseven days after lesion.The cholinergic lesion-induced transient up-regulation of cortical glucose transporters anddeoxyglucose uptake reflects an increased glucose demand in regions depleted by acetylcholinesuggesting functional links between cortical cholinergic activity and glucose metabolism incholinoceptive target regions.