Abstracts

Inhibition of Seizure Activity Through Increased Glutamate Uptake.

Abstract number : 1.111
Submission category :
Year : 2000
Submission ID : 1216
Source : www.aesnet.org
Presentation date : 12/2/2000 12:00:00 AM
Published date : Dec 1, 2000, 06:00 AM

Authors :
Margaret L Sutherland, Tom Yao, Stephen H Williams, George Washington Univ, Washington, DC; Vanderbilt Univ, Nashville, TN.

For many years, experimental and clinical evidence have linked excitatory amino acids (EAAs) with epilepsy and seizure occurrence. Although the ionotropic and metabotropic glutamate receptors have traditionally been considered as potential targets for anti-epileptic therapies, we present evidence that glutamate transport is also a key element in determining the onset, severity and progression of seizure activity. To accomplish this goal we generated a transgenic murine model of EAAT2 glutamate transporter overexpression. EAAT2 is the principal glial subtype of glutamate transporter expressed in the adult CNS. Down regulation of EAAT2 mRNA and protein occurs in patients with Ammon's horn sclerosis, as well as in convulsant-induced models of temporal lobe epilepsy. In the EAAT2 transgenic model, overexpression of EAAT2 is driven by the astrocyte-specific promoter GFAP and results in a 3 to 5 fold increase in cortical and hippocampal synaptosomal glutamate uptake. Cortical electroencephalographic recording demonstrates that in two independently derived lines of EAAT2 transgenic mice seizure activity, following i.p. administration of 30 mg/kg kainic acid, was reduced by 80% compared with recordings from age matched wild-type animals. In the 602 transgenic line, overexpression of EAAT2 glutamate transporter also resulted in a delay in seizure onset, while the frequency of discharge was significantly decreased in the 642 transgenic line. In both EAAT2 transgenic lines increased glutamate uptake resulted in a 70- 80% reduction in latent excitotoxic cell death and inhibition of astrogliosis. Our results suggest that increased glutamate uptake can have both short and long term effects in the seizure sequelae. Supported by NIMH (MLS).