We searched PubMed for articles published in English between Jan 1, 1944, to May 31, 2014, with the search terms “migraine”, “migraine AND model”, and “cortical spreading depression”. We also searched reference lists of identified articles for other relevant reports. The final reference list was generated according to relevance to the topics covered in the Review.
ReviewMigraine pathophysiology: lessons from mouse models and human genetics
Introduction
Migraine is a common, multifactorial, neurovascular disorder with major individual and societal effects.1, 2, 3 Migraine affects roughly 15% of people4 and is typically characterised by disabling episodes of severe headache accompanied by nausea, vomiting, and hypersensitivity to light, sound, and smell for up to 3 days (migraine without aura).5 In a third of patients, attacks might be associated with transient focal neurological aura symptoms (migraine with aura); it has been suggested that migraine with and without aura are distinct disorders (panel 1).5 Once a migraine attack has started, the mechanisms underlying migraine aura and headache are reasonably well understood (Figure 1, Figure 2, Figure 3). Aura is most likely caused by cortical spreading depression, and headache by activation of the trigeminovascular system and associated release of calcitonin gene-related peptide (CGRP).19 On the basis of animal experiments, cortical spreading depression has also been proposed as a possible trigger activating the trigeminovascular system, thus providing a possible pathophysiological link between aura and headache.
Attack frequency differs widely in patients, from one per year to several per week. Half the patients have attacks at least twice a month, 25% have them at least weekly, and about 3% have chronic migraine with headaches occurring at least half the time.3, 27 Thus, on average, every day at least 24 million people in the European Union and North America have migraines, making the condition one of the most disabling and expensive medical complaints worldwide.4, 28, 29
For clinical, epidemiological, and genetic studies, migraineurs are defined as people who have had at least five episodes of migraine without aura or two episodes of migraine with aura ever in their life.5 Clinical expression is believed to be determined by genetic factors for up to 60%,7, 30 and for the remaining 40% by non-genetic endogenous (eg, age, [sex-related] hormonal fluctuations, and comorbid diseases) and exogenous (eg, head trauma, fatigue, and changes in sleeping pattern) risk-modulating factors.
Migraine, depression, and epilepsy are comorbid conditions, in that the presence of one of these diseases increases the risk of development of one or both of the others, and vice versa.31, 32 The disorders also share common treatments, as specific antiepileptic drugs are also effective in migraine and depression,33 and the antidepressant drug amitriptyline is frequently used in migraine prevention.34 Taken together, these observations suggest common mechanisms, most likely shared genetic factors, for migraine, epilepsy, and depression.
Migraineurs are also at increased risk of cerebral35, 36, 37, 38 and myocardial39 infarction, suggesting systemic involvement of the vasculature in migraine. A genome-wide association study (GWAS) in the Women's Health Study in over 5000 women with migraine with information on cardiovascular disease suggested that genetic factors play a part in both diseases, although no specific gene variants were identified.40 Although common genetic factors for migraine and stroke have not yet been identified at the general population level, at least two genes (NOTCH3 and TREX1) are known that cause both migraine and ischaemic stroke.
Despite our knowledge of the mechanisms after initiation of the attack, there is an unmet need for treatments to prevent migraine attacks and to stop the condition from becoming chronic. The main reasons for this dearth of options are the low understanding of how migraine attacks are triggered and initiated, which raises questions such as why do migraines so often continue to recur throughout life, why in a proportion of patients do attacks recur more frequently (up to several times a week), and finally why in so many patients do attacks stop recurring at older age? In this Review, we will try to answer some of these questions by reviewing the present status of the genetics and molecular neurobiology of migraine and the growing evidence that the brains of people with migraines might be hyperexcitable and more susceptible to cortical spreading depression. These findings might open up new avenues for improved migraine prophylactic treatments and might also further the understanding of the pathology of migraine-comorbid disorders such as epilepsy, depression, and stroke.
Section snippets
Genetic studies in patients with migraine
GWAS can identify disease-associated gene variants and thus, more importantly, markers of novel pathways. In migraine, three large GWAS8, 9, 10 and a subsequent meta-analysis11 identified 13 susceptibility gene variants (table 1). These variants point at genes that cluster into five pathways: glutamatergic neurotransmission; synapse development and plasticity; pain sensing; metalloproteinases; and vasculature and metabolism. The ascertainment of the contribution of individual variants in these
Transgenic mouse models of FHM1
Two knock-in mouse models of FHM1 have been generated to study the functional outcomes of FHM mutations and to identify pathophysiological mechanisms potentially involved in FHM and hence possibly also in non-hemiplegic migraine.82, 83 By use of a gene-targeting approach, the human pathogenic Arg192Gln or Ser218Leu missense mutation were inserted into the mouse orthologous Cacna1a by homologous recombination. Arg192Gln was chosen because it is associated with a mild pure FHM phenotype without
Mechanisms for migraine comorbid diseases
Migraine with aura is associated with increased risk of ischaemic stroke, particularly in women;37, 140 migraine might even be a greater risk factor for stroke than hypertension and diabetes.141 Studies in FHM1 mice have suggested that neuroexcitatory mechanisms implicated in migraine might also increase vulnerability to ischaemic injury.142 Ischaemic peri-infarct depolarisations similar to cortical spreading depression occurred earlier and more frequently in experimental stroke in FHM1 mice
Mouse models for other FHM genes
A knock-in mouse model for FHM2 was generated by introducing the human Trp887Arg missense mutation in the orthologous Atp1a2 mouse gene.144 Mutant protein concentration in the brain was strongly decreased in heterozygous mutant mice and almost undetectable in homozygous mutants (which died immediately after birth).144 As in FHM1 mice, in mice with heterozygous FHM2 the in vivo cortical spreading depression triggering threshold was decreased and cortical spreading depression propagation velocity
A final common pathway for FHM
Although all three FHM genes encode for different proteins with distinct functions and involvement in different pathways, the seemingly diverging mechanisms ultimately converge into one common pathway: increased synaptic concentration of the excitatory neurotransmitter glutamate leading to cerebral hyperexcitability and enhanced susceptibility to cortical spreading depression (figure 4). FHM1 CaV2·1 CACNA1A gain-of-function mutations cause increased neuronal release of glutamate82, 83, 84 and
From FHM to migraine with and without aura
FHM has been used as a model to identify possible pathways for the more common forms of migraine with aura and migraine without aura. The question now is whether and to what extent mechanisms identified for FHM are also involved in non-hemiplegic migraine. Enhanced susceptibility to cortical spreading depression is a common characteristic of transgenic mouse models for monogenic migraine syndromes (table 2), and there is growing, albeit circumstantial, evidence that FHM-like mechanisms might
Conclusions and future directions
Migraine is one of the most prevalent, disabling, undertreated, and costly medical conditions worldwide. Research efforts are focusing on disentangling the mechanisms that trigger and initiate migraine attacks as novel targets for prophylactic treatments for migraine attacks and to prevent the transition to chronic migraine.
Clinical and genetic studies have shown that migraine is a multifactorial disorder with complex interaction between multiple predisposing genetic and modulating non-genetic
Search strategy and selection criteria
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