Traumatic Brain Injury Down‐Regulates Glial Glutamate Transporter (GLT‐1 and GLAST) Proteins in Rat Brain

Abstract

Excess activation of NMDA receptors is felt to participate in secondary neuronal damage after traumatic brain injury (TBI). Increased extracellular glutamate is active in this process and may result from either increased release or decreased reuptake. The two high‐affinity sodium‐dependent glial transporters [glutamate transporter 1 (GLT‐1) and glutamate aspartate transporter (GLAST)] mediate the bulk of glutamate transport. We studied the protein levels of GLT‐1 and GLAST in the brains of rats after controlled cortical impact‐induced TBI. With use of subtype‐specific antibodies, GLT‐1 and GLAST proteins were quantitated by immunoblotting in the ipsilateral and contralateral cortex at 2, 6, 24, 72, and 168 h after the injury. Sham‐operated rats served as control. TBI resulted in a significant decrease in GLT‐1 (by 20–45%; p < 0.05) and GLAST (by 30–50%; p < 0.05) protein levels between 6 and 72 h after the injury. d‐[3H]Aspartate binding also decreased significantly (by 30–50%; p < 0.05) between 6 and 72 h after the injury. Decreased glial glutamate transporter function may contribute to the increased extracellular glutamate that may mediate the excitotoxic neuronal damage after TBI. This is a first report showing altered levels of glutamate transporter proteins after TBI.

Differential Effects of Corticostriatal and Thalamostriatal Deafferentation on Expression of the Glutamate Transporter GLT1 in the Rat Striatum

“…Regional deafferentation experiments have shown that the levels of expression of the primarily glial EAA transporter proteins GLAST and GLT1 in various cerebral structures are dependent on EAA innervation (Ginsberg et al, 1995, 1996; Levy et al, 1995; Raghavendra Rao et al, 1998). This interpretation is in line with the recent finding that cortical neurons induce expression of the transporter protein GLT1 and increase expression of GLAST in astrocyte culture (Swanson et al., 1997).…”

“…The differences between the effects of the cortical lesion on the GLT1 protein and its mRNA expression in the spared cortical areas may be explained as discussed above concerning the striatal responses. Interestingly, it has been recently shown that expression of the primarily glial glutamate transporters GLT1 and GLAST in the cortex also decreases significantly between 6 and 72 h but not 168 h after traumatic brain injury (Raghavendra Rao et al, 1998). On the other hand, changes in GLT1 mRNA levels in the parietoinsular cortex and the striatum are opposite at 5 DPL but similar at longer survival times, suggesting that the mechanisms underlying the lesionmediated changes in GLT1 transcripts or the time course of the changes may differ among cerebral regions.…”

Insights into the metabolic response to traumatic brain injury as revealed by 13C NMR spectroscopy

“…Reactive astrocytes play dual roles following injury, one that may result in a detrimental increase in glutamate excitotoxicity or inflammation, the other being brain protection or repair (Laird et al, 2008). A transient down regulation of glutamate transporters GLT-1, GLT-1v, and GLAST on astrocytes after experimental (Rao et al, 1998, 2001; Yi and Hazell, 2006) and human TBI (van Landeghem et al, 2006; Beschorner et al, 2007) may well contribute to the injury process. However, ablation of reactive astrocytes following experimental CCI in transgenic mice resulted in greater loss of cortical tissue and inflammation, suggesting an essential protective role for astrocytes after TBI (Myer et al, 2006).…”

Preconditioning with Cortical Spreading Depression Decreases Intraischemic Cerebral Glutamate Levels and Down‐Regulates Excitatory Amino Acid Transporters EAAT1 and EAAT2 from Rat Cerebal Cortex Plasma Membranes

“…Knockout studies have shown that EAAT2 and, to a lesser extent, EAAT1 are responsible for the bulk of glutamate clearance in the rat cerebral cortex (Rothstein et al, 1996). It is interesting that EAAT2 and EAAT1, but not EAAT3, appear to be regulatable proteins (Ginsberg et al, 1995 ; Rothstein, 1996 ; Raghavendra Rao et al, 1998). Down‐regulation of both EAAT2 and EAAT1 has been observed in crude homogenized membranes following regional deafferentation within the rat cerebrum (Ginsberg et al, 1995).…”