Abstracts

Elevated glutamate levels have been reported in several epilepsy models. The electrophysiological changes that occur when transporter function is disrupted in experimental models of epilepsy have not been examined. The freeze-induced model of cortical dysplasia results in abnormal lamination of cortical structures associated with hyperexcitability in the region adjacent to the microsulcus. Here we used this model to test the role of glutamate transporters in synaptic transmission in the hyperexcitable region., Focal freeze lesions were induced in postnatal day (PN) 0 Sprague-Dawley rats using methods described previously. In freeze-lesioned cortex, recordings of layer II/III pyramidal cells were obtained 0.3-1.5 mm lateral to the microsulcus. Synaptic responses were evoked with a bipolar stimulating electrode (twisted pair of 25 mm Formvar insulated nichrome wires) positioned 150-200 [mu]m below the recording pipette. Stimuli were current pulses 10-100 [mu]A in amplitude and 50-100 ms in duration. A stimulation frequency of 0.05 Hz was used. The glutamate uptake antagonists DL-threo-[beta]-benzylozyaspartic acid (TBOA) and dihydokainate (DHK) were bath applied., TBOA prolonged postsynaptic currents (PSCs) and decreased the threshold for evoking spontaneous epileptiform activity in lesioned cortex. Uptake inhibition also induced an increase in holding current in the dysplastic cortex. In contrast, responses in sham operated and control animals were not affected. The effect of blocking uptake was mediated primarily by the glia glutamate transporter (GLT-1) since the selective GLT-1 blocker DHK mimicked the effects of TBOA. The increases in the holding current suggested that glutamate was accumulating extracellularly and activating ionotropic glutamate receptors. The increase in excitability following uptake inhibition appeared to be mediated by N-methyl-D-aspartate (NMDA) receptors since prior application of D-(-)-2-amino-5-phosphonovaleric acid (APV) prevented TBOA-induced effects and TBOA-induced changes were reversed by APV. In the freeze-lesioned cortex spontaneous epileptiform activity does not occur at a high rate. Under control conditions, the probability for the occurrence of spontaneous discharge was 0.09 [plusmn] 0.06 (n = 22) which increased significantly to 0.59 [plusmn] 0.1 (n = 22) when TBOA was applied., These results indicate that glutamate transporter function is altered in rat focal cortical dysplasia and these changes contribute to the observed hyperexcitability. Alteration in transporter function could result in increasing extracellular glutamate concentrations and over activation of NMDA receptors during neuronal activity., (Supported by NS22373.)