Electrographic Features of Spontaneous Recurrent Seizures in a Mouse Model of Extended Hippocampal Kindling

Abstract

Epilepsy is a chronic neurological disorder characterized by spontaneous recurrent seizures (SRS) and comorbidities. Kindling through repetitive brief stimulation of a limbic structure is a commonly used model of temporal lobe epilepsy. Particularly, extended kindling over a period up to a few months can induce SRS, which may simulate slowly evolving epileptogenesis of temporal lobe epilepsy. Currently, electroencephalographic (EEG) features of SRS in rodent models of extended kindling remain to be detailed. We explored this using a mouse model of extended hippocampal kindling. Intracranial EEG recordings were made from the kindled hippocampus and unstimulated hippocampal, neocortical, piriform, entorhinal, or thalamic area in individual mice. Spontaneous EEG discharges with concurrent low-voltage fast onsets were observed from the two corresponding areas in nearly all SRS detected, irrespective of associated motor seizures. Examined in brain slices, epileptiform discharges were induced by alkaline artificial cerebrospinal fluid in the hippocampal CA3, piriform and entorhinal cortical areas of extended kindled mice but not control mice. Together, these in vivo and in vitro observations suggest that the epileptic activity involving a macroscopic network may generate concurrent discharges in forebrain areas and initiate SRS in hippocampally kindled mice.

Clustering of Spontaneous Recurrent Seizures in a Mouse Model of Extended Hippocampal Kindling

“…This difference may be partly attributable to the more frequent SRS events observed in hippocampal kindled mice compared with other SRS induction methods. In our experiments, 6-14 SRS events per day were generally observed in individual mice, and SRS-free 24-h periods were rarely observed (35,38). However, there were limitations in our continuous 24h EEG-video monitoring, which might fail to reveal SRS-free 24-h periods that might occur sporadically or infrequently in individual mice.…”

“…Electrode implantation and extended kindling were performed, as previously described (36)(37)(38). Each mouse was implanted with two pairs of twisted-wire bipolar electrodes that were made of polyimide-insulated and tip-exposed stainless-steel wires (outer diameter 0.125 mm; Plastics One, Virginia, USA).…”

“…We used a train of stimuli (60 Hz for 2 seconds) for hippocampal kindling (35,36,38,(43)(44)(45). Briefly, constant current pulses (monophasic waveforms with pulse duration of 0.5 ms and current intensities of 10-150 µA) were generated by a Grass stimulator and delivered through a photoelectric isolation unit (model S88, Grass Medical Instruments, Warwick, Rhode Island, USA).…”

“…Continuous 24-h EEG-video monitoring was performed, as previously described (35)(36)(37)(38). Briefly, each mouse was placed in a modified cage with food and water ad libitum.…”

“…Thus far, no reports have described seizure clusters in rodent models of extended kindling. We attempted to provide information in this area using a mouse model of extended hippocampal kindling that was developed in our laboratory ( 36 – 38 ). Considering that temporal lobe epilepsy is highly diverse in etiologies and electro-clinical manifestations ( 39 , 40 ), our present observations may complement the previous studies (see references above) that characterize seizure clusters in other models of temporal lobe epilepsy.…”