Electrophysiologic Analysis of a Chronic Seizure Model After Unilateral Hippocampal KA Injection

Authors

  • Anatol Bragin,

    1. Department of Neurology, UCLA School of Medicine, Los Angeles, California, U.S.A.
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    • Permanent address of Dr. Bragin: Institute of Experimental and Theoretical Biophysics, Puschino, Russia.

  • Jerome Engel Jr.,

    Corresponding author
    1. Department of Neurology, UCLA School of Medicine, Los Angeles, California, U.S.A.
    2. Department of Neurobiology, UCLA School of Medicine, Los Angeles, California, U.S.A.
    3. Brain Research Institute, UCLA School of Medicine, Los Angeles, California, U.S.A.
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  • Charles L. Wilson,

    1. Department of Neurology, UCLA School of Medicine, Los Angeles, California, U.S.A.
    2. Brain Research Institute, UCLA School of Medicine, Los Angeles, California, U.S.A.
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  • Elizabeth Vizentin,

    1. Department of Neurology, UCLA School of Medicine, Los Angeles, California, U.S.A.
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  • Gary W. Mathern

    1. Department of Neurology, UCLA School of Medicine, Los Angeles, California, U.S.A.
    2. Division of Neurosurgery, UCLA School of Medicine, Los Angeles, California, U.S.A.
    3. Brain Research Institute, UCLA School of Medicine, Los Angeles, California, U.S.A.
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Address correspondence and reprint requests to Dr. J. Engel, Jr. at Reed Neurological Research Center, Department of Neurology, 710 Westwood Plaza, UCLA School of Medicine, Los Angeles, CA 40095-1769. U.S.A. E-mil: engel@ucla.edu.

Abstract

Summary: Purpose: Unilateral intrahippocampal injections of kainic acid (KA) in rats produce spontaneous recurrent limbic seizures and morphologic changes in hippocampus that resemble hippocampal sclerosis in patients with medically refractory mesial temporal lobe epilepsy (MTLE), that form of temporal lobe epilepsy (TLE) associated with hippocampal sclerosis. Interictal in vivo electrophysiologic studies have revealed high-frequency (250-500 Hz) oscillations, termed fast ripples (FRs). These oscillations may uniquely occur in or adjacent to the site of hippocampal KA injection, in areas that generate spontaneous seizures. Similar field potentials also have been demonstrated in the epileptogenic region of patients with TLE. We have now characterized ictal electrographic patterns in this rat model for comparison with those in human TLE and begun to evaluate the role of FRs in the transition to ictus in the KA-treated rat.

Methods: Rats received unilateral intrahippocampal injections of KA and, after the development of spontaneous seizures, were implanted with multiple fixed and moveable microelectrodes for single unit, field potential, and EEG recording. They were then monitored by using video-EEG telemetry for several weeks to capture and evaluate electrographic and behavioral seizure types. Results were correlated with Timm's stain demonstration of mossy fiber sprouting.

Results: Low-voltage fast (LVF) and hypersynchronous electrographic ictal-onset patterns were seen in the KA-treated rat that resembled similar ictal-onset patterns in patients with TLE. Hypersynchronous, but not LVF, ictal discharges were associated with recurrent FRs. As in the human, hypersynchronous ictal onsets originated predominantly in hippocampus, whereas LVF ictal onsets more often involved extrahippocampal structures. LVF ictal onsets occurred during wakefulness or paradoxical sleep and were usually associated with motor behavior, whereas hypersynchronous ictal onsets occurred during slow-wave sleep or periods of immobility and were not associated with motor behavior unless there was transition to another ictal electrographic pattern. Mossy fiber sprouting did not correlate with the frequency of ictal EEG discharges exhibited by each rat but was greater in those rats that demonstrated frequent behavioral seizures.

Conclusions: The electrographic features of spontaneous seizures in the KA-treated rat resemble those of patients with medically refractory TLE with respect to EEG pattern and localization. Our data suggest that hypersynchronous ictal onsets represent epileptogenic disturbances in hippocampal circuits, whereas LVF ictal onsets may involve extrahippocampal areas having more direct connections to the motor system. Hypersynchronous seizures may involve the same neuronal mechanisms that generate interictal FRs.

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