Dataset Information

Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

ABSTRACT: Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the ?1A 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 h 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.

SUBMITTER: Eising E

PROVIDER: S-EPMC5390001 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

Eising Else E Shyti Reinald R 't Hoen Peter A C PAC Vijfhuizen Lisanne S LS Huisman Sjoerd M H SMH Broos Ludo A M LAM Mahfouz Ahmed A Reinders Marcel J T MJT Ferrari Michel D MD Tolner Else A EA de Vries Boukje B van den Maagdenberg Arn M J M AMJM

Molecular neurobiology 20160331 4

Familial hemiplegic migraine type 1 (FHM1) is a rare monogenic subtype of migraine with aura caused by mutations in CACNA1A that encodes the α<sub>1A</sub> subunit of voltage-gated Ca<sub>V</sub>2.1 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 ...[more]

PMID: 27032388

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Project description:Functioning of the glymphatic system, a network of paravascular tunnels through which cortical interstitial solutes are cleared from the brain, has recently been linked to sleep and traumatic brain injury, both of which can affect the progression of migraine. This led us to investigate the connection between migraine and the glymphatic system. Taking advantage of a novel in vivo method we developed using two-photon microscopy to visualize the paravascular space (PVS) in naive uninjected mice, we show that a single wave of cortical spreading depression (CSD), an animal model of migraine aura, induces a rapid and nearly complete closure of the PVS around surface as well as penetrating cortical arteries and veins lasting several minutes, and gradually recovering over 30 min. A temporal mismatch between the constriction or dilation of the blood vessel lumen and the closure of the PVS suggests that this closure is not likely to result from changes in vessel diameter. We also show that CSD impairs glymphatic flow, as indicated by the reduced rate at which intraparenchymally injected dye was cleared from the cortex to the PVS. This is the first observation of a PVS closure in connection with an abnormal cortical event that underlies a neurological disorder. More specifically, the findings demonstrate a link between the glymphatic system and migraine, and suggest a novel mechanism for regulation of glymphatic flow.SIGNIFICANCE STATEMENT Impairment of brain solute clearance through the recently described glymphatic system has been linked with traumatic brain injury, prolonged wakefulness, and aging. This paper shows that cortical spreading depression, the neural correlate of migraine aura, closes the paravascular space and impairs glymphatic flow. This closure holds the potential to define a novel mechanism for regulation of glymphatic flow. It also implicates the glymphatic system in the altered cortical and endothelial functioning of the migraine brain.

Dataset Information

Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

Publications

Cortical Spreading Depression Causes Unique Dysregulation of Inflammatory Pathways in a Transgenic Mouse Model of Migraine.

Similar Datasets

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