Abstracts

Rationale: While seizures in epileptic patients are often infrequent, long-term intracranial recordings demonstrate far more frequent abnormal electrical discharges between seizures called interictal spikes. The direct impact and role of interictal spikes on generating seizures in patients with epilepsy is controversial. Previous studies on human epileptic brain tissues in our laboratory have shown a ‘final common pathway’ of specific genes that are upregulated at human epileptic foci. Surprisingly, the levels of expression of these genes did not correlate with seizure frequency, but correlated precisely with the amount of interictal spiking. Methods: In order to determine whether interictal spiking has a direct causal effect on these expression changes, we utilized a rat model of interictal spiking that develops slowly over time after focal administration of tetanus toxin into the somatosensory cortex. Following injection, six epidural electrodes were implanted to monitor epileptic activities over several weeks. Results: Focal spikes at the injection site could be reliably detected 1-2 weeks after injection and increased in both amplitude and frequency over time. After several weeks, spikes began to cluster together in groups, and seizures could eventually be produced. Interictal spiking in the absence of detected seizures was correlated with sustained induction of signaling pathways, including phosphoCREB, in superficial cortical neurons. In situ hybridization studies showed a similar increase in expression of genes encoding synaptic plasticity markers and transcription factors in these superficial layers that we previously found to be induced in human epileptic neocortex. This occurred on the spiking side of the brain relative to the contralateral hemisphere and to vehicle-injected controls. Conclusions: These results suggest that interictal spiking alone is sufficient to induce persistent changes in the signaling pathways and genes induced in human epileptic neocortex. These genes and pathways, many of which have known roles in synaptic plasticity, are potential targets for generating novel therapeutic agents to treat human epilepsy.