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 remained unresolved. Treatment with pyrithiamine, a central thiamine antagonist, resulted in a 71 and 55% decrease in protein levels of the astrocyte glutamate transporters GLT-1 and GLAST, respectively, by immunoblotting in the medial thalamus of day 14 symptomatic rats at loss of righting reflexes. These changes occurred prior to the onset of convulsions and pannecrosis. Loss of both GLT-1 and GLAST transporter sites was also confirmed in this region of the thalamus at the symptomatic stage using immunohistochemical methods. In contrast, no change in either transporter protein was detected in the non-vulnerable frontal parietal cortex. These effects are selective; protein levels of the astrocyte GABA transporter GAT-3 were unaffected in the medial thalamus. In addition, astrocyte-specific glial fibrillary acidic protein (GFAP) content was unchanged in this brain region, suggesting that astrocytes 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 transporters occurs within 48 h prior to loss of righting reflexes. Finally, GLT-1 content was positively correlated with levels of the neurofilament protein alpha-internexin, suggesting that early neuronal drop-out may contribute to the down-regulation of this glutamate transporter and subsequent pannecrosis. 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 thalamic structures to thiamine deficiency-induced cell death.
Hazell
A S
AS
Neuroscience Research Unit, Hôpital Saint-Luc, CHUM, University of Montreal, Montreal, Quebec, Canada.
Rao
K V
KV
Danbolt
N C
NC
Pow
D V
DV
Butterworth
R F
RF
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001253:Astrocytes / Q000502:physiology*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins; D008297:Male; D010296:Parietal Lobe / Q000378:metabolism; D011745:Pyrithiamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013223:Statistics as Topic; D013788:Thalamus / Q000378:metabolism*; D013832:Thiamine Deficiency / Q000139:chemically induced / Q000378:metabolism; D014899:Wernicke Encephalopathy / Q000139:chemically induced / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D000963:Antimetabolites; D002352:Carrier Proteins; D007381:Intermediate Filament Proteins; C046643:alpha-internexin; D018698:Glutamic Acid; D011745:Pyrithiamine