Abstracts

Medial temporal lobe sclerosis (MTS) is associated with a wide variety of anatomical and physiological changes in the hippocampus of epileptic patients including hypometabolism. We hypothesized that a consequence of this hypometabolism would be an inability to sustain repetitive synaptic activity given the high energetic cost of synaptic transmission. We performed intracellular recordings from dentate granule cells in slices prepared from resected hippocampi from patients with TLE. Recordings were made from a total of 72 cells from 31 patients; 22 with typical MTS and 9 with other pathologies. We examined the responses to 1, 5 and 10 Hz stimulus trains delivered to the outer molecular layer. We also measured the IPSP conductance. In 15 of these patients, the resected pes hippocampi was used to measure the N-acetyl-aspartate to total creatine ratio (NAA/Cr). Quantitative cell counts were used for pathological assessment and correlative analyses. There was no significant change in the synaptic response following 1 Hz stimulation in either of the patient groups. However, at higher frequencies we noted a pronounced depression in the synaptic response in MTLE compared to non-MTLE patients measured as the percent change in the area of the synaptic response (10 Hz:-34.5 [plusmn] 6.5% comparison; -59.6 [plusmn] 4.1% MTS, p[lt]0.05. 5 Hz: -5.8 [plusmn] 11.7 comparison; -37.6 [plusmn] 5.4, MTS, p[lt]0.01). This effect was also associated with a significant decrease in the number of action potentials evoked during the trains for both frequencies. Moreover, there was no correlation between the synaptic depression and the IPSP conductance at either frequency. The synaptic depression correlated highly with the total cell loss, p[lt]0.005 10 Hz; [lt]0.05, 5 Hz). Finally, we found that the levels of NAA/Cr, a marker of neuronal mitochondrial function, was significantly correlated with the degree of synaptic depression at both frequencies, p[lt]0.05,0.03, respectively. These data indicate that is a profound synaptic depression at frequencies greater than 5 Hz is a consistent feature of the epileptic human dentate gyrus. This depression is not mediated by somatic inhibition; however we cannot rule out a contribution by either enhanced dendritic inhibition or neuromodulators. The significant correlation between this synaptic depression with a metabolic variable supports the hypothesis that part of the depression may reflect an inability of metabolically impaired tissue to support sustained synaptic activity as reflected by the decrease neuronal mitochondrial function as reflected by decreased levels of NAA/Cr. (Supported by NINDS grants R01 NS45792 to AW: PO139092 to AW, DDS and OAP and NIA grant AG00795 to PRP.)