INCREASED GLUTAMATE TRANSPORTER ACTIVITY IS NEUROPROTECTIVE IN A TEMPORAL LOBE EPILEPSY MODEL
Abstract number :
2.016
Submission category :
Year :
2002
Submission ID :
1477
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Margaret L. Sutherland, Stephen H. Williams. Pharmacology, George Washington University, Washington, DC
RATIONALE: Recent evidence suggests that temporal lobe epilepsy is associated with changes in the level of expression of EAAT2 (Glt-1), the predominant CNS glutamate transporter. Similar findings have been made in experimental models of temporal lobe epilepsy. One important role the transporters may play is to prevent glutamate levels from rising to neurotoxic levels during seizure activity. This could be particularly important in temporal lobe epilepsy where cell loss from the hippocampus can occur (Ammon[scquote]s horn sclerosis). We have tested the hypothesis that enhanced glutamate transporter activity might subserve a neuroprotective role under seizure conditions using a mouse EAAT2 overexpression model.
METHODS: To examine the role of glutamate transporters in a temporal lobe epilepsy model, we generated a transgenic murine model of EAAT2 glutamate transporter overexpression. In the EAAT2 transgenic model, overexpression of EAAT2 was driven by the astrocyte-specific promoter GFAP and resulted in a 3 to 5 fold increase in cortical and hippocampal synaptosomal glutamate uptake.
RESULTS: Transgenic animals exhibited higher survival rates following i.p. injection of 30mg/kg kainic acid than age matched wild type litter mates. Histological analysis, 7 days post seizure induction, indicated that in both EAAT2 transgenic lines increased glutamate uptake resulted in a 70- 80% reduction in latent excitotoxic cell death compared with wild type animals, as determined by TUNEL analysis. Immediate early gene induction and inhibition of astrogliosis were also significantly reduced in EAAT2 transgenic animals compared to wild type. To determine if electrical activity was effected we recorded surface cortical electroencephalographic activity prior to and during seizures. In two independently derived lines of EAAT2 transgenic mice seizure activity following administration of 30 mg/kg kainic acid was reduced by 80% compared with recordings from age matched wild-type animals.
CONCLUSIONS: Our results suggest that increased glutamate uptake can have both short and long term effects in the seizure sequelae. We find that EAAT2 overexpression significantly reduces excitotoxicity in the kainic acid model. Interestingly, overexpression of the glutamate transporter also reduces the severity of the paroxysmal electrical events that occur during the seizure suggesting that glutamate may play a role in controlling excitability in glutamatergic circuits during hypersynchronous activity.
[Supported by: grants from NINDS (NS042854) and MDA (MLS).]