Genetic insights into migraine and glutamate: a protagonist driving the headache

JOURNAL OF THE NEUROLOGICAL SCIENCES

卷:367

Review

Gasparini, Claudia F.¹  Smith, Robert A.²  Griffiths, Lyn R.² 

[1] Griffith Univ Gold Coast, Menzies Hlth Inst Queensland, Parklands Dr, Southport, Qld 4222, Australia

[2] Queensland Univ Technol, Inst Hlth & Biomed Innovat, Sch Biomed Sci, Genom Res Ctr, Musk Ave, Kelvin Grove, Qld 4059, Australia

关键词: Migraine;    Migraine with aura;    Migraine without aura;    Glutamate;    PRRT2;    GRIA1;    Cortical spreading depression;    RNA editing;    GWAS;   

DOI  :  10.1016/j.jns.2016.06.016

来源: Elsevier

【 摘 要 】

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 GRIM. 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. (C) 2016 Elsevier B.V. All rights reserved.

【 授权许可】

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