Migraine and glutamate: a genetic insight

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Migraine and glutamate: a genetic insight

In the developed world, migraine is a complex polygenic disorder that continues to be a great source of morbidity with an occurrence of 12% in the Caucasian population. In migraine pathophysiology, the genetic and pharmacological studies have exposed the glutamate pathway. In the drug discovery process, glutamate remains a “hot” target which profoundly impacts brain circuits that regulate core symptom domains in a range of neuropsychiatric situations.

Glutamate has been involved in cortical spreading depression (CSD), a phenomenon responsible for migraine with aura and in animal models carrying FHM mutations. The genotyping case-control studies have depicted an association between glutamate receptor genes, namely, GRIA1 and GRIA3 with migraine with indirect supporting evidence from GWAS. New evidence localizes PRRT2 at glutamatergic synapses and reveals it affects glutamate signaling and glutamate receptor activity by interactions with GRIA1. Recently, glutamate-system defects have also been involved in a novel FHM2 ATP1A2 disease-mutation mouse model. The neurophysiological findings also support a part for glutamate in cortical excitability.

The glutamate receptor diversity and regulation is escalated by the post-translational mechanisms of RNA editing and miRNAs along with the existence of multiple genes to choreograph the functions of fast-signaling glutamatergic neurons and glutamate receptor diversity.

The neurogenic mechanisms in migraine pathology and the first genome-wide related locus for migraine on chromosome X is implicated by the ongoing genetic studies, GWAS and meta-analysis. Hence, in addition to glutamate modulating therapies, the kynurenine pathway has evolved as a candidate for involvement in migraine pathophysiology. Thus, in the review mentioned here, the discussions have been made on the recent genetic evidence and glutamate modulating therapies that bear on the hypothesis that a glutamatergic mechanism may have a role in migraine susceptibility.

J Neurol Sci.
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