ABSTRACT
Cortical spreading depression (CSD), an underlying mechanism of migraine aura, propagates to the hippocampus, and might explain hippocampusassociated symptoms during migraine attack. We hypothesised that this process is, some parts, mediated by NMDA receptors. By using a rat model, CSD was elicited by solid KCl for 45 minutes prior to electrophysiological and quantitative analyses. The result from electrophysiological study was the ratio of glutamate NMDA receptor 2A and 2B subunits (GluN2A/B). Total NMDA receptor response was isolated using an AMPA antagonist, prior to a GluN2B receptor antagonist. The GluN2A/B ratio was calculated by dividing the remaining NMDA-mediated field-excitatory synaptic potentials (fEPSP) with the subtracted difference of NMDAmediated fEPSP. Western blot analysis of the hippocampus was performed to confirm the quantitative change of GluN2A/B ratio. In hippocampal slice study (n = 12), the GluN2A/B ratio of hippocampal fEPSP was significantly increased in CSD group. Western blot analysis (n = 30) revealed an increase in GluN2A subunits and a decrease in GluN2B subunits in the hippocampus ipsilateral to the CSD induction. Our current study revealed that GluN2A/B ratio was shown to be elevated following CSD stimulation by increasing the total number of GluN2A while reducing the total number of GluN2B subunits. This ratio was demonstrated to be associated with synaptic plasticity of the hippocampus in numerous studies. In conclusion, we showed that CSD increased GluN2A/B ratio, in turn, would result in altered synaptic plasticity. Our findings provide a probable implication on the correlation of migraine aura and hippocampusassociated symptoms.
ABSTRACT
OBJECTIVE: To investigate the alteration of hippocampal long-term plasticity and basal synaptic transmission induced by repetitive cortical spreading depressions (CSDs). BACKGROUND: There is a relationship between migraine aura and amnesia attack. CSD, a state underlying migraine attacks, may be responsible for hippocampus-related symptoms. However, the precise role of CSD on hippocampal activity has not been investigated. METHODS: Male Wistar rats were divided into CSD and control groups. Repetitive CSDs were induced in vivo by topical application of solid KCl. Forty-five minutes later, the ipsilateral hippocampus was removed, and hippocampal slices were prepared for a series of electrophysiological studies. RESULTS: Repetitive CSDs led to a decrease in the magnitude of long-term potentiation in the hippocampus. CSD also reduced hippocampal synaptic efficacy, as shown by a reduction in post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor responses. In contrast, the post-synaptic N-methyl-d-aspartate receptor responses remained unchanged. In addition, there were no changes in paired-pulse profiles between the groups, indicating that CSD did not induce any presynaptic alterations. CONCLUSION: These findings suggest that a reduction of post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor responses is the mechanism responsible for impaired hippocampal long-term potentiation induced by CSD.
