Pathophysiological Characteristics Associated With Epileptogenesis in Human Hippocampal Sclerosis

Mesial temporal lobe epilepsy (MTLE) is the most frequent focal epileptic syndrome in adults, and the majority of seizures originate primarily from the hippocampus. The resected hippocampal tissue often shows severe neuronal loss, a condition referred to as hippocampal sclerosis (HS). In order to understand hippocampal epileptogenesis in MTLE, it seems important to clarify any discrepancies between the clinical and pathological features of affected patients. Here we investigated epileptiform activities ex vivo using living hippocampal tissue taken from patients with MTLE. Flavoprotein fluorescence imaging and local field potential recordings revealed that epileptiform activities developed from the subiculum. Moreover, physiological and morphological experiments revealed possible impairment of K+ clearance in the subiculum affected by HS. Stimulation of mossy fibers induced recurrent trans-synaptic activity in the granule cell layer of the dentate gyrus, suggesting that mossy fiber sprouting in HS also contributes to the epileptogenic mechanism. These results indicate that pathophysiological alterations involving the subiculum and dentate gyrus could be responsible for epileptogenesis in patients with MTLE. •Enhanced activity including HFO was detected in subiculum samples from patients with MTLE.•Decreased Kir4.1 channel activity in astrocytes was considered to induce hyperexcitability in the subiculum in HS.•MFS was observed in granule cells of the DG only in HS patients and was correlated with the degree of dispersion. In most cases of mesial temporal lobe epilepsy (MTLE), seizure onset can be detected accurately in the hippocampus and the prognosis after surgical resection is good, suggesting that epileptogenesis originates in the hippocampus. We physiologically investigated surgically resected human hippocampal tissue ex vivo, and found enhanced activities including HFO in the subiculum. Failure of the potassium buffering system in astrocytes was considered to contribute to the epileptic activity in the hippocampus affected by severe sclerosis. Our results suggest that different pathophysiological mechanisms may underlie MTLE depending on the degree of hippocampal sclerosis.