New directions in migraine

Abstract

Migraine is a highly prevalent neurological disorder imparting a major burden on health care around the world. The primary pathology may be a state of hyperresponsiveness of the nervous system, but the molecular mechanisms are yet to be fully elucidated. We could now be at a watershed moment in this respect, as the genetic loci associated with typical forms of migraine are being revealed. The genetic discoveries are the latest step in the evolution of our understanding of migraine, which was initially considered a cerebrovascular condition, then a neuroinflammatory process and now primarily a neurogenic disorder. Indeed, the genetic findings, which have revealed ion channels and transporter mutations as causative of migraine, are a powerful argument for the neurogenic basis of migraine. Modulations of ion channels leading to amelioration of the migraine 'hyperresponsive' brain represent attractive targets for drug discovery. There lies ahead an exciting and rapidly progressing phase of migraine translational research, and in this review we highlight recent genetic findings and consider how these may affect the future of migraine neurobiology and therapy.

Figure 1

Migraine mutations affecting the central glutamate synapse. Increased Ca2+ influx caused by familial hemiplegic migraine subtype 1 (FHM1) associated mutations in Cav2.1 channels enhance glutamate release from presynaptic terminals. Loss of Na+/K+ ATPase function, as seen in FHM2, indirectly reduces astrocyte uptake of glutamate, resulting in increased levels of the neurotransmitter in the synaptic cleft. FHM3 associated mutations can reduce firing of inhibitory interneurons or potentiate presynaptic action potential generation. Mutations in SLC4A4 inhibit glia-mediated acid secretion and thus free N-methyl-D-aspartate (NMDA) receptors from proton-mediated inhibition. Activity of EAAT1, the major glutamate transporter in the brain, is directly affected by a mutation in its sequence and indirectly by upregulation of MTDH, a likely consequence of a reported mutation in rs1835740. LRP1 has a role in glutamate signalling and has been shown to directly modulate NMDA-dependent calcium currents in vitro.

Figure 2

Neuronal circuitry in migraine pain generation. Cortical spreading depression (CSD) triggers plasma protein extravasation from dural blood vessels, which in turn activates trigeminal (TG) afferents. Multiple mutations have been found in familial and sporadic migraine that could reduce the threshold for firing of TG neurons, either directly by affecting neuronal excitability or indirectly by modulating local glia activity. Signals are transduced to the trigeminal nucleus caudalis (TNC), which receives several modulatory inputs from other areas of the brainstem, such as the periaqueductal gray (PAG), the locus coeruleus (LC) and the raphe nuclei (RN). These areas have been proposed as sites of dysfunction in migraine. The TNC projects to rostral brain areas, where the perception of pain is generated.