Parenchymal Neuroinflammation in Familial Hemiplegic Migraine Type 1 Transgenic Mouse Model After Cortical Spreading Depression
Özet
Cortical spreading depression (CSD) is the likely cause of the migraine aura. CSD causes a signaling pathway between stressed neurons and trigeminal afferents via transient opening of neuronal Pannexin-1 (Panx1) mega-channels followed by high mobility group box 1 (HMGB1) release from neurons and nuclear factor kappa B (NF-κB) relocation in astrocytes. Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in the CACNA1A gene. Transgenic knock-in mice that carry human FHM1 missense mutations R192Q or S218L exhibit an increased susceptibility to CSD and other features relevant to migraine. Here, we investigated the basal and experimentally CSD-induced parenchymal neuroinflammation in female mutant mice and wild-type (WT), and studied whether CSD-induced inflammation shows a particular regional pattern, which may highlight areas that are particularly relevant to disease pathology. Our data revealed a basal parenchymal neuroinflammatory state in R192Q mutant mice as revealed by higher neuronal HMGB1 release and NF-κB activation in astrocytes. There was a different regional distribution pattern in the inflammatory signaling upon CSD in the frontal/parietal cortices and striatum/thalamus of both R192Q and WT mice. In addition, in mutant mice this inflammatory pattern was bilateral. There was a rise in HMGB1 release in subcortical areas of mutant mice compared to that in WT mice which was particularly pronounced in thalamus compared to striatum. Immunohistochemical data was supported by Western blotting in which cerebrospinal fluid (CSF) HMGB1 amount and brain nuclear translocation of NF-κB was studied. S218L mutant mice showed more HMGB1 in CSF compared to WT and brain NF-κB translocation was increased in mutant and WT CSD and mutant sham-operated groups compared to WT sham. Electrophysiological analysis showed that CSD speed is higher in mutant groups, however CSD half maximum amplitude duration and CSD frequency did not change significantly between groups. Derivative of CSD depolarisation phase demonstrated that both derivative of the first CSD and subsequent CSDs were increased in FHM1 mutant groups compared to WT mice reflecting the hyperexcitability of mutant ones. Here for the first time in the literature, we presented that there is basal parenchymal neuroinflammation in R192Q mutant mice brain both in cortical and subcortical levels. Our findings indicate that CSD triggers parenchymal inflammatory processes in both WT and mutant mouse brains, which is mostly ipsilateral to the side of CSD induction in WT mice, and bilateral in the mutant mice. Future studies may indicate if basal neuroinflammation contributes to cortical hyperexcitability seen in FHM1 mutants in addition to the increased neuronal calcium influx or increased calcium and glutamate cause basal neuroinflammation. These findings indicate that CSD-induced parenchymal neuroinflammation spreads through cortex, striatum, and thalamus of both hemispheres in genetically susceptible brains, which may explain the prolonged hemiplegia, coma, and seizure phenotype in this variant of migraine with aura.
