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) results in chronic neuronal death in the hippocampus. In the normal brain, glutamate 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 mediates 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 injury in rats infused with GLT-1 antisense oligodeoxynucleotides (ODNs) exacerbated the hippocampal neuronal death and mortality, compared with the GLT-1 sense/random ODN-infused controls. At 7 days after the injury, hippocampal neuronal numbers were significantly lower in the CA1 (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 GLT-1 sense/random ODN-infused controls. This study suggested a role for GLT-1 dysfunction in promoting the hippocampal neuronal death after traumatic brain injury.
Rao
V L
VL
Department of Neurological Surgery, University of Wisconsin-Madison, WI, USA. Vemugant@neurosurg.wisc.edu
Dogan
A
A
Bowen
K K
KK
Todd
K G
KG
Dempsey
R J
RJ
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001930:Brain Injuries / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology; D015536:Down-Regulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014949:Wounds, Nonpenetrating / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger