Selective down-regulation of the astrocyte glutamate transporters GLT-1 and GLAST within the medial thalamus in experimental Wernicke's encephalopathy

Although earlier studies on thiamine deficiency have reported increases in extracellular glutamate concentration in the thalamus, a vulnerable region of the brain in this disorder, the mechanism by which this occurs has remai ned unresolved. Treatment with pyrithiamine, a central thiamine antagonist, resulted in a 71 and 55% decrease in protein levels of the astrocyte gluta mate transporters GLT-1 and GLAST, respectively, by immunoblotting in the m edial thalamus of day 14 symptomatic rats at loss of righting reflexes. The se changes occurred prior to the onset of convulsions and pannecrosis. Loss of both GLT-1 and GLAST transporter sites was also confirmed in this regio n of the thalamus at the symptomatic stage using immunohistochemical method s. In contrast, no change in either transporter protein was detected in the non-vulnerable frontal parietal cortex. These effects are selective; prote in levels of the astrocyte GABA transporter GAT-3 were unaffected in the me dial thalamus. In addition, astrocyte-specific glial fibrillary acidic prot ein (GFAP) content was unchanged in this brain region, suggesting that astr ocytes are spared in this disorder. Loss of GLT-1 or GLAST protein was not observed on day 12 of treatment, indicating that down-regulation of these t ransporters occurs within 48 h prior to loss of righting reflexes. Finally, GLT-1 content was positively correlated with levels of the neurofilament p rotein alpha -internexin, suggesting that early neuronal drop-out may contr ibute to the down-regulation of this glutamate transporter and subsequent p annecrosis. A selective, focal loss of GLT-1 and GLAST transporter proteins provides a rational explanation for the increase in interstitial glutamate levels, and may play a major role in the selective vulnerability of thalam ic structures to thiamine deficiency-induced cell death.