title: Glial glutamate transporter GLT-1 down-regulation precedes delayed neuronal death in gerbil hippocampus following transient global cerebral ischemia.
abstract: Glial (GLT-1 and GLAST) and neuronal (EAAC1) high-affinity transporters mediate the sodium dependent glutamate reuptake in mammalian brain. Their dysfunction leads to neuronal damage by allowing glutamate to remain in the synaptic cleft for a longer duration. The purpose of the present study is to understand their contribution to the ischemic delayed neuronal death seen in gerbil hippocampus following transient global cerebral ischemia. The protein levels of these three transporters were studied by immunoblotting as a function of reperfusion time (6 h to 7 days) following a 10 min occlusion of bilateral common carotid arteries in gerbils. In the vulnerable hippocampus, there was a significant decrease in the protein levels of GLT-1 (by 36-46%, P < 0.05; between 1 and 3 days of reperfusion) and EAAC1 (by 42-68%, P < 0.05; between 1 and 7 days of reperfusion). Histopathological evaluation showed no neuronal loss up to 2 days of reperfusion but an extensive neuronal loss (by approximately 84%, P < 0.01) at 7 days of reperfusion in the hippocampal CA1 region. The time frame of GLT-1 dysfunction (1-3 days of reperfusion) precedes the initiation of delayed neuronal death (2-3 days of reperfusion). This suggests GLT-1 dysfunction as a contributing factor for the hippocampal neuronal death following transient global cerebral ischemia. Furthermore, decreased EAAC1 levels may contribute to GABAergic dysfunction and excitatory/inhibitory imbalance following transient global ischemia.
authors.affiliation: Department of Neurological Surgery, University of Wisconsin-Madison, F4/309 Clinical Science Center, 53792, USA. vemugant@neurosurg.wisc.edu
authors.forename: V L
authors.initials: VL
authors.lastname: Raghavendra Rao
authors.forename: A M
authors.initials: AM
authors.lastname: Rao
authors.forename: A
authors.initials: A
authors.lastname: Dogan
authors.forename: K K
authors.initials: KK
authors.lastname: Bowen
authors.forename: J
authors.initials: J
authors.lastname: Hatcher
authors.forename: J D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: R J
authors.initials: RJ
authors.lastname: Dempsey
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001692:Biological Transport; D015153:Blotting, Western; D016923:Cell Death; D002540:Cerebral Cortex / Q000378:metabolism; D015536:Down-Regulation; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006652:Histological Techniques; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000473:pathology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG