Assessment of spontaneous seizure activity and evoked hippocampal responses in freely-behaving rats treated with low-dose systemic injections of kainate

Abstract

Human temporal lobe epilepsy is associated with complex partial seizures that can produce secondarily generalized seizures and motor convulsions. This condition is also coupled with hippocampal sclerosis and mossy fiber sprouting in the inner molecular layer of the dentate gyrus. In many patients with temporal lobe epilepsy, the seizures and convulsions occur following a latent period after an initial injury and may progressively increase in frequency for much of the patient's life. However, the mechanisms and time course that cause epileptogenesis are not well defined. In this study, we used the kainate-treated rat as an animal model for temporal lobe epilepsy to test the following hypotheses: 1) rats treated with multiple, low-dose intraperitoneal injections of kainate will develop a chronic epileptic state following a latent period after the initial treatment; 2) like some humans with epilepsy, rats with kainate-induced epilepsy will exhibit more spontaneous motor seizures during inactivity than during activity; 3) kainate treatment will induce both electrographic status epilepticus and permanent abnormal electrographic events; and 4) hippocampal inhibition will be restored within the first week after kainate treatment, when minimal, if any, mossy fiber sprouting has occurred in the inner molecular layer of the dentate gyrus. Our results show that rats treated with multiple low-dose injections of kainate developed a chronic epileptic state characterized by a latent period before the onset of chronic motor seizures. We also found that the frequency of spontaneous motor seizures depends primarily on activity state (i.e., inactivity) rather than time of day, which is similar to some humans with epilepsy. Electrographic status epilepticus was recorded in all rats during kainate treatment, and interictal spikes were observed as early as one day after kainate treatment. Finally, chronic electrophysiological recordings from the dentate gyrus suggest that inhibition may be reduced in some rats treated with kainate; but when inhibition was reduced, partial to full recovery occurred within one week, when little or no mossy fiber sprouting had developed. Thus, kainate-treated rats have similar behavioral, anatomical, and electrophysiological characteristics to those seen in humans with temporal lobe epilepsy.