Antisense knockdown of the glial glutamate transporter GLT-1 exacerbates hippocampal neuronal damage following traumatic injury to rat brain

Traumatic injury to rat brain induced by controlled cortical impact (CCI) r esults in chronic neuronal death in the hippocampus. In the normal brain, g lutamate transporters actively clear the glutamate released synaptically to prevent receptor overactivation and excitotoxicity. Glutamate transporter 1 (GLT-1) is the most abundant and active glutamate transporter, which medi ates the bulk of glutamate uptake. CCI injury significantly decreased GLT-1 mRNA (by 49-66%, P < 0.05) and protein (by 29-44%, P < 0.05) levels in the ipsilateral hippocampus, compared with either the respective contralateral hippocampus or the sham-operated control, 24-72 h after the injury, CCI in jury in rats infused with GLT-1 antisense oligodeoxynucleotides (ODNs) exac erbated the hippocampal neuronal death and mortality, compared with the GLT -1 sense/random ODN-infused controls. At 7 days after the injury, hippocamp al neuronal numbers were significantly lower in the CAI (reduced by 32%, P < 0.05), CA2 (by 45%, P < 0.01), CA3 (by 68%, P < 0.01) and dentate gyrus ( by 31%, P < 0.05) in GLT-1 antisense ODN-infused rats, compared with the GL T-1 sense/random ODN-infused controls. This study suggested a role for GLT- 1 dysfunction in promoting the hippocampal neuronal death after traumatic b rain injury.