Spreading depolarization is followed by seizure-like activation of the hippocampus: potential mechanism of migraine-aura triggered seizures.

Abstract

BACKGROUND: Propagation of spreading depolarization (SD), a wave of transient cellular depolarization, over the cerebral cortex drives migraine aura symptoms. Growing evidence suggests that hippocampus, brain region involved in regulation of mood and cognition, also contributes to pathogenesis of migraine. Hippocampus has highly inhomogeneous functional anatomy with strong dorsoventral difference in functional and network properties. We hypothesized that cerebral dysfunction induced by SD also varies within the hippocampus and studied characteristics and effects of SD in the dorsal and ventral hippocampus of awake animals. Given high susceptibility of the hippocampus to seizures, we focused on excitatory effects of SD. METHODS: Unilateral SD was induced by a pinprick of the dorsal hippocampus in freely behaving rats. In electrophysiological experiments, local field potentials were recorded bilaterally in different sites along the dorsoventral axis of the hippocampus; propagation patterns, electrographic manifestations and excitatory effects of SD were evaluated. In separate experiments, effect of hippocampal SD on behavior was assessed. RESULTS: SD waveforms varied depending on local cytoarchitecture of hippocampal zones (CA, dentate gyrus and fiber-rich areas), irrespectively of their dorsoventral level. In the dentate gyrus, unusual double-wave SDs were recorded. Reaching ventral hippocampus, unilateral SD triggered a bilateral seizure-like discharge recruited both ipsilateral (affected by SD) and contralateral (unaffected by SD) sides. The post-SD activation of the ventral hippocampus had striking behavioral manifestation - a bout of wet dog shakes. CONCLUSIONS: This is the first experimental evidence that SD can trigger seizure-like activity in particular regions of awake non-epileptic brain. We suggest that the phenomenon may be relevant to mechanisms of migraine-aura triggered seizures (migralepsy).