The intrahippocampal kainate model of temporal lobe epilepsy revisited: Epileptogenesis, behavioral and cognitive alterations, pharmacological response, and hippoccampal damage in epileptic rats

Abstract

Systemic or intracerebral (e.g., intrahippocampal or intraamygdalar) administration of kainate, a potent neurotoxic analog of glutamate, is widely used to induce status epilepticus (SE) and subsequent development of epilepsy in rats. However, in apparent contrast to systemic administration, following intracerebral injection the proportion of rats that have been observed to generate spontaneous recurrent seizures (SRS) and the frequency of the SRS are comparatively low. More recently, it has been shown that these problems can be resolved by injecting kainate into the dorsal hippocampus of awake rats, thus avoiding the insult-modifying effects of anesthesia, which had often been used for intracerebral injection of this convulsant in previous studies. For further characterization of this model, we injected kainate (0.4 μg) unilaterally into the CA3 of the posterior hippocampus in awake rats, which induced limbic SE (ranging from 4 to 20 h) in all rats without mortality. Repeated video-EEG monitoring (24h/day, 7 days/week) for periods of 1-2.5 weeks from 1 to 8 months after SE demonstrated that 91% of the rats developed epilepsy, and that seizure frequency significantly increased over the course of the disease. Epilepsy was associated with increased behavioral excitability and impaired learning and memory in a water maze, most likely as a result of hippocampal pathology, which was characterized by extensive neuronal loss in CA3 and dentate hilus and dispersion of granule cells in the ipsilateral hippocampus. A drug trial with phenobarbital showed that all epileptic rats used in this trial responded to treatment with suppression of SRS. The data substantiate that intrahippocampal kainate injection in awake rats offers an excellent model of human temporal lobe epilepsy and indicate that this model may have particular advantages for studying mechanisms of injury-induced epilepsy and comorbidities as targets for antiepileptic and antiepileptogenic therapies.