Highlights
- •Genetic evidence implicates the glutamatergic system in migraine attacks.
- •Biochemical studies show peripheral changes in the metabolism of glutamate.
- •Glutamate-modulating therapies have shown promise in treating migraine symptoms.
- •Glutamate and its receptors remains a “hot” target for drug discovery.
Abstract
Migraine is a complex polygenic disorder that continues to be a great source of morbidity
in the developed world with a prevalence of 12% in the Caucasian population. Genetic
and pharmacological studies have implicated the glutamate pathway in migraine pathophysiology.
Glutamate profoundly impacts brain circuits that regulate core symptom domains in
a range of neuropsychiatric conditions and thus remains a “hot” target for drug discovery.
Glutamate has been implicated in cortical spreading depression (CSD), the phenomenon
responsible for migraine with aura and in animal models carrying FHM mutations. Genotyping
case-control studies have shown 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 shows it affects glutamate signalling and glutamate
receptor activity via interactions with GRIA1. Glutamate-system defects have also been recently implicated
in a novel FHM2 ATP1A2 disease-mutation mouse model. Adding to the growing evidence
neurophysiological findings support a role for glutamate in cortical excitability.
In addition to the existence of multiple genes to choreograph the functions of fast-signalling
glutamatergic neurons, glutamate receptor diversity and regulation is further increased
by the post-translational mechanisms of RNA editing and miRNAs. Ongoing genetic studies,
GWAS and meta-analysis implicate neurogenic mechanisms in migraine pathology and the
first genome-wide associated locus for migraine on chromosome X. Finally, in addition
to glutamate modulating therapies, the kynurenine pathway has emerged as a candidate
for involvement in migraine pathophysiology. In this review we discuss recent genetic
evidence and glutamate modulating therapies that bear on the hypothesis that a glutamatergic
mechanism may be involved in migraine susceptibility.
Keywords
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Article info
Publication history
Published online: June 09, 2016
Accepted:
June 8,
2016
Received in revised form:
May 11,
2016
Received:
November 27,
2015
Identification
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© 2016 Elsevier B.V. All rights reserved.
