Temporal lobe epilepsy where and how do spontaneous seizures initiate? [electronic resource]

Epilepsy is one of the most common serious neurological disorders, affecting 0.4% to 1.0% of the world's population. Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults. TLE is also one of the most difficult types of epilepsy to control; TLE is often refractory to the medical treatments, and patients may require more invasive surgical treatments. The pilocarpine-treated rat model is used frequently to investigate TLE. However, where and how seizures initiate in this model is poorly understood. To better understand where seizures initiate in the pilocarpine model, we implanted 32 recording depth electrodes and investigated the electrographic seizure activity of various temporal lobe structures, including the septum, dorsomedial thalamus, amygdala, olfactory cortex, dorsal and ventral hippocampus, substantia nigra, entorhinal cortex, and ventral subiculum. We found that the ventral hippocampus and ventral subiculum displayed the earliest electrographic seizure activity. The amygdala, olfactory cortex, and septum occasionally displayed early seizure activities, but these observations were not statistically significant. The similarities in onset sites of spontaneous seizures in patients with temporal lobe epilepsy and pilocarpine model suggest that the hippocampal formation is important for seizure initiation in both pilocarpine-treated rats and humans. Given the similarities between seizure initiation sites in pilocarpine-treated rats and TLE patients, we next sought to investigate the mechanisms of spontaneous seizure initiation in our model. Although the mechanisms underlying spontaneous seizure initiation are poorly understood, we speculated that inhibitory interneurons are likely to be involved. Therefore, we examined local field potentials and unit activity of single, putative inhibitory interneurons in the dorsal hippocampal formation, including dentate gyrus, CA1, CA3, and subiculum in epileptic pilocarpine-treated rats. We found that seconds-to-minutes before the onset of a spontaneous seizures, average firing rates of interneurons increased significantly in all subregions of the hippocampal formation. Subicular interneurons displayed the earliest and largest average preictal increase, whereas CA3 interneurons displayed the least change in preictal activity. Changes in interneuron activity may in part due to increased theta activity in the local field potential, but at least some preictal changes in interneuron activity were theta-independent. Furthermore, we identified putative interneuron classes in CA1, including two parvalbumin-positive basket cells, two oriens-lacunosum-moleculare cells, two bistratified cells, and an ivy cell, and examined their preictal activities. Putative bistratified cells increased firing rate significantly above the baseline whereas a putative ivy cell decreased firing rate prior to seizure onset. Putative OLM cells showed a little to no change in firing rate prior to seizure onset. Finally, one putative basket cell increased firing rate significantly above the baseline whereas another putative basket cell decreased its firing rate significantly below the baseline prior to seizure onset. Collectively, this work highlights the possible roles of hippocampal interneurons in initiation and propagation of spontaneous seizures in the pilocarpine model of temporal lobe epilepsy. These findings will not only expand our general understanding of mechanisms of spontaneous seizure initiation but could also have implications for the development of therapeutic interventions for TLE patients.

Advisor: Buckmaster Paul S. primary advisor. Thesis advisor
Knudsen Eric I. advisor. Thesis advisor
Parvizi Josef
Prince David