Rapid onset of a kainate-induced mirror focus in rat hippocampus is mediated by contralateral AMPA receptors

Abstract

The development of an epileptic "mirror" focus in an area of the brain contralateral to the primary epileptic focus typically evolves over days in the experimental setting after status epilepticus or electrical kindling of the primary focal region. In contrast, we observed the rapid development of an apparent mirror focus in the contralateral hippocampus following microinjection of kainic acid (KA) in the ipsilateral hippocampus in rats. Using multisite intracranial recordings, local field potentials were recorded in anesthetized adult male rats using electrodes implanted in the CA3 region of both hippocampi and in the anteromedial nucleus of the thalamus. Epileptogenesis was induced by microinjection of KA in the ipsilateral CA3 region. Development of seizures was followed under three experimental perturbations to the contralateral hippocampus: (A) no treatment, (B) pre-treatment with microinjection of the AMPA/Kainate receptor antagonist CNQX, and (C) pre-treatment with microinjection of the selective kainate receptor antagonist UBP 301. Both control and UBP 301 groups had seizures preferentially originate in the contralateral hippocampus appearing within ten minutes of KA injection. In contrast, the CNQX group had seizures preferentially originate in the ipsilateral hippocampus. By tracking the order of seizure onset, the probability that a hippocampal seizure would propagate across commissural fibers prior to any thalamic seizure activity was significantly reduced in the CNQX group compared to control and UBP groups suggesting that the AMPA receptor mediated component responsible for mirror focus development was also necessary for the spread of ictal activity via the commissural fibers. Understanding how a complex circuit in the brain develops may be critical to uncovering ways of either disrupting its development or treating its effects. The rapid appearance of a contralateral mirror focus via AMPA receptors in a limbic epilepsy model might be the mechanism by which a putative long-term mirror focus is established in vivo and may also underlie how secondary generalization progresses in some cases.