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RNA profiling by deepSAGE sequencing in the cortex of a migraine mouse model after induction of cortical spreading depression

ABSTRACT: Familial Hemiplegic Migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the a1A subunit of voltage-gated CaV2.1 calcium channels. Transgenic knock-in mice that carry the human FHM1 R192Q missense mutation (“FHM1 R192Q mice”) exhibit an increased susceptibility to cortical spreading depression (CSD), the mechanism underlying migraine aura. Here we analysed gene expression profiles from isolated cortical tissue of FHM1 R192Q mice 24 hours after experimentally induced CSD in order to identify molecular pathways affected by CSD. Gene expression profiles were generated using deep Serial Analysis of Gene Expression sequencing. Our data reveal a signature of inflammatory signalling upon CSD in the cortex of both mutant and wild-type mice. However, only in the brains of FHM1 R192Q mice specific genes are up-regulated in response to CSD that are implicated in interferon-related inflammatory signalling. Our findings show that CSD modulates inflammatory processes in both wild-type and mutant brains, but that an additional unique inflammatory signature becomes expressed after CSD in a relevant mouse model of migraine.

ORGANISM(S): Mus musculus

PROVIDER: GSE67933 | GEO | 2016/04/14

SECONDARY ACCESSION(S): PRJNA281239

REPOSITORIES: GEO

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Project description:Background：CircRNAs are non-coding RNA molecules that have recently been described and shown to regulate miRNA functionality. While recent studies have suggested such circRNAs to be associated with pain related diseases in humans, no comprehensive migraine-related circRNA profiles have been generated and there is currently no clear understanding of whether they can serve as regulators of migraine pathology. Methods:We initially conducted a circRNA microarray analysis of the plasma of migraine patients and healthy controls. Based upon these data, we then selected 8 differentially expressed circRNAs and confirmed their expression in more migraine patient plasma samples via real-time PCR. We then performed functional and pathway enrichment analyses. Lastly, using a robust rank aggregation approach, we constructed a ceRNA network according to predicted circRNA–miRNA and miRNA–mRNA pairs in these migraine patient samples. Results:we were able to detect 2039 circRNAs in our patient samples, with and 794 of 1245 these circRNAs being up- and down-regulated in migraine patients relative to controls, respectively (fold change ≥1.5, P < 0.01). A qRT-PCR analysis confirmed that the expression of hsa_circRNA_100236, hsa_circRNA_102413, and hsa_circRNA_000367 was significantly enhanced in migraine patients, whereas the expression of hsa_circRNA_103809, hsa_circRNA_103670, and hsa_circRNA_101833 was significantly reduced in these individuals relative to healthy controls. We found these differentially regulated circRNAs to be associated with numerous predicted biological processes, with enrichment analyses suggesting that they may modulate PI3K-Akt signaling so as to promote inflammation to drive migraine development. However, further research will be needed to formally test these mechanistic possibilities and to validate these circRNAs as potential biomarkers of migraine patients.Conclusions: our results offer new potential insights into the mechanistic basis of this condition, and suggest that hsa_circRNA_000367 and hsa_circRNA_102413 may offer value as regulators of migraine pathology.

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RNA profiling by deepSAGE sequencing in the cortex of a migraine mouse model after induction of cortical spreading depression

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