Excitatory Inhibitory Balance

Review
Feature Review
Migraine: a disorder of brain excitatoryinhibitory balance?

Dania Vecchia1 and Daniela Pietrobon1,2
1 2
Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy CNR Institute of Neuroscience, 35121 Padova, Italy
Migraine is a common disabling brain disorder whose key manifestations are recurrent attacks of unilateral headache and interictal hypersensitivity to sensory stimuli. Migraine arises from a primary brain dysfunction that leads to episodic activation and sensitization of the trigeminovascular pain pathway and as a consequence to headache. Major open issues concern the molecular and cellular mechanisms of the primary brain dysfunction(s) and of migraine pain. We review here our current understanding of these mechanisms, focusing on recent advances regarding migraine genetics, headache mechanisms, and the primary brain dysfunction(s) underlying migraine onset and susceptibility to cortical spreading depression, the neurophysiological correlate of migraine aura. We also discuss insights obtained from the functional analysis of familial hemiplegic migraine mouse models. Introduction Migraine is a common episodic neurological disorder with complex pathophysiology that manifests itself as recurrent attacks of typically throbbing and unilateral, often severe, headache with associated features such as nausea, phonophobia and/or photophobia; in a third of patients the headache is preceded by transient neurological symptoms that are most frequently visual but may involve other senses (migraine with aura: MA) [1] (Table 1). Migraine is a public health problem of great impact upon both the individual and society. It is one of the 20 most disabling diseases (according to World Health Organization ranking [2]). Furthermore, it is remarkably common (e.g., it affects 17% of females and 8% of males in the European population [3]) and very costly (EUR 18.5 billion/year in Europe [4]). It is generally believed that migraine headache depends on the activation and sensitization of the trigeminovascular pain pathway [57] (Figure 1), and that cortical spreading depression (CSD)-like events underlie migraine aura [5,8,9]. CSD can be induced in animals by focal stimulation of the cerebral cortex and consists of a slowly propagating (26 mm/min) wave of strong neuronal and glial depolarization whose mechanisms of initiation and propagation remain unclear [10,11]. It is also generally recognized that most migraine attacks start in the brain. This is suggested by the premonitory symptoms (such as difculty with
Corresponding author: Pietrobon, D. (daniela.pietrobon@unipd.it). Keywords: migraine; trigeminovascular pain; spreading depression; excitatory inhibitory balance; channelopathy..
speech and reading, increased emotionality, sensory hypersensitivity) which in many patients are highly predictive of the attack although occurring up to 12 h before it [12] as well as by the nature of some typical migraine triggers (e.g., stress, sleep deprivation, oversleeping, hunger and/or prolonged sensory stimulation) [13]. Psychophysical and neurophysiological studies have provided clear evidence that in the period between attacks migraineurs show hypersensitivity to sensory stimuli and abnormal processing of sensory information, characterized by increased amplitudes and reduced habituation of evoked and event-related potentials [14,15]. The nature and mechanisms of the primary brain dysfunction(s) leading to the onset of a migraine attack, to CSD susceptibility, and to episodic activation of the trigeminovascular pain pathway remain largely unknown and are major outstanding issues to be addressed in furthering our understanding of the neurobiology of migraine. Other important open questions concern the mechanisms of migraine pain. Here, we review recent advances regarding (i) the genetics of migraine; (ii) the mechanisms of migraine headache, focusing on the roles of meningeal inammation, calcitonin gene-related peptide (CGRP), central sensitization, and dysfunctional central control of pain; and (iii) the mechanisms of the primary brain dysfunction(s) leading to episodic activation of the trigeminovascular pain pathway. We also discuss insights into these mechanisms obtained from the functional analysis of mouse models of familial hemiplegic migraine (FHM), a rare monogenic autosomal dominant form of MA. Genetics of migraine Migraine is a complex genetic disorder, with heritability estimates as high as 50% and probable polygenic multifactorial inheritance [16,17]. The complexity of the disease has hampered the identication of common susceptibility variants; the lack of consensus on most of the identied susceptibility loci probably reects clinical and genetic heterogeneity [16,17]. Most of our current understanding of genetic factors underlying migraine comes from studies of FHM. Three causative genes, all encoding ion channels or transporters, have been identied [16,1821]. Additional FHM genes certainly exist and remain to be identied [22]. Apart from the motor weakness or hemiparesis during aura, typical FHM attacks resemble MA attacks (Table 1) and both
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0166-2236/$ see front matter 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tins.2012.04.007 Trends in Neurosciences, August 2012, Vol. 35, No. 8
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Figure 1. Schematic illustration of important neuronal structures and connections in the trigeminovascular pathways involved in migraine headache. (a) Afferent pathways. The central projections of the trigeminal ganglion (TG) neurons that innervate the meninges terminate in the so-called trigeminocervical complex (TCC) comprising the C1 C2 dorsal horns of the cervical spinal cord and the caudal division of the spinal trigeminal nucleus (TNC) (C-fibers mainly in superficial layers; A-d fibers in deep layers). The TCC makes direct ascending connections with different areas in the brainstem (including the superior salivatory nucleus, SSN, the ventrolateral periacqueductal grey, vlPAG, the nucleus cuneiformis, NCF) and with higher structures including several hypothalamic and thalamic nuclei, which in turn make ascending connections with the cortex [99,144,145]. Stimulation of the dural afferents in experimental animals results in activation of second-order trigeminovascular neurons (mainly in laminae I, II and V) in the TCC, as well as neurons in several brainstem (e.g., SSN, vlPAG, rostral ventromedial medulla, RVM), hypothalamic and thalamic (in particular the ventroposteriomedial, VPM and posterior, Po) nuclei receiving connections from the TCC [60,73,92,105,111] ([5,99] for review and older references). Dura-sensitive VPM thalamic neurons project mainly in the trigeminal primary and secondary somatosensory (S1, S2) and the insular (Ins) cortex (in the so-called pain matrix areas), and thus are likely to play a role in the perception of the headache; whereas trigeminovascular Po thalamic neurons project well beyond the pain matrix into non-trigeminal S1, as well as auditory, visual, retrosplenial, ectorhinal, and parietal association cortices, and thus are likely to contribute to other aspects of the migraine experience which include disturbances in neurological functions involved in vision, auditory, memory, motor, and cognitive performance [105,145]. The trigeminovascular projections to specific hypothalamic and brainstem nuclei are likely to contribute to other aspects of the complex migraine symptomatology such as loss of appetite, sleepiness, irritability, stress, pursuit of solitude, and autonomic symptoms [99]. (b) Efferent modulatory pathways. The TCC receives descending projections from brainstem and hypothalamic nociceptive modulatory nuclei that may mediate descending modulation of trigeminovascular nociceptive traffic [99]. Experimental evidence of modulation of TCC response to dural stimulation has been obtained for vlPAG, the nucleus raphae magnus in the RVM, the posterior hypothalamus (PH) and the A11 dopaminergic hypothalamic nucleus (reviewed in [99]). The TCC also receives descending cortical projections from layer 5 pyramidal cells of the contralateral S1 (innervating mainly neurons in deep laminae IIIV) and caudal Ins cortex (innervating exclusively laminae I and II) [111]. It should be noted that there are other afferent and efferent connections: this diagram only illustrates those mentioned in the text.
types of attacks may alternate in patients and co-occur within families, suggesting that FHM and MA may be part of the same spectrum and may share some pathogenetic mechanisms. Some FHM patients can also have atypical severe attacks and/or permanent cerebellar symptoms [16,21]. FHM1 is caused by missense mutations in CACNA1A, the gene encoding the pore-forming subunit of neuronal CaV2.1 (P/Q-type) voltage-gated calcium channels [18,23]. These calcium channels are widely expressed in the nervous system, including all brain regions implicated in the pathogenesis of migraine. CaV2.1 channels play a dominant role in controlling neurotransmitter release, particularly at central synapses. Their somatodendritic localization points to additional postsynaptic roles, such as in neural excitability [23,24]. Analysis of the single channel properties of mutant recombinant human CaV2.1 channels and of the P/Q-type calcium current in different neurons [including cortical and trigeminal ganglion (TG) neurons] of knockin mice
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carrying FHM1 mutations revealed that the mutations produce gain-of-function of CaV2.1 channels, mainly due to increased channel open probability and channel activation at lower voltages [23,2531]. However, the gain-offunction effect may be dependent on the specic CaV2.1 splice variant and/or auxiliary subunit [32,33]. In TG neurons of FHM1 knockin mice the P/Q-type calcium current was increased in a subtype of neuron (that does not innervate the dura) but was unaltered in capsaicin-sensitive neurons innervating the dura; congruently, the FHM1 mutation did not alter depolarization-evoked CGRP release from the dura, but increased CGRP release from trigeminal ganglia [31]. In the cerebral cortex of FHM1 knockin mice, excitatory synaptic transmission was enhanced as a consequence of increased action potential-evoked glutamate release at pyramidal cell synapses; in striking contrast, inhibitory neurotransmission at fast-spiking (FS) interneuron synapses was unaltered (despite being initiated by P/Q-type calcium channels) [26] (Figure 2a). Neuron subtype- and synapse-specic effects may help to explain why a
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Table 1. Main features of migraine without aura (MO), migraine with aura (MA), and familial hemiplegic migraine (FHM)
Type MO Headache symptoms Headache attacks (472 h in duration) with at least two of: Unilateral location Throbbing Moderate or severe pain intensity Aggravation by physical activity And at least one of: Nausea and/or vomiting Photophobia and phonophobia Headache as in MO begins during the aura or follows aura (within 1 h) Aura symptoms None
MA
At least one of: Fully reversible visual symptoms (e.g., ickering lights, spots, lines and/or loss of vision) Fully reversible sensory symptoms (i.e., pins and needles and/or numbness) Fully reversible dysphasic speech disturbance Each aura symptom lasts 5 and 60 min Fully reversible motor weakness and at least one of the MA aura symptoms Each aura symptom lasts 5 min and <24 h
FHM
Headache as in MA
calcium channel that is widely expressed in the nervous system produces the specic dysfunctions that cause FHM (the implications for specic migraine mechanisms are discussed in the sections following). FHM2 is caused by (mainly missense) mutations in ATP1A2, the gene encoding the a2 subunit of the Na+/K+ ATPase [16,19]. In the brain, this isoform is expressed primarily in neurons during embryonic development and at time of birth but almost exclusively in astrocytes in the adult; its colocalization and functional coupling with glial glutamate transporters in astrocytic processes surrounding glutamatergic synapses suggests a specic role in glutamate clearance [3436] (Figure 2a), whereas its colocalization with the Na+/Ca2+ exchanger in microdomains that overlie subplasmalemmal endoplasmic reticulum suggests a specic role in the regulation of intracellular Ca2+ [21]. FHM2 mutations cause complete or partial loss-offunction of recombinant Na+/K+ ATPases due to loss or reduction of catalytic activity (and/or more subtle functional impairments) or impairment of plasma membrane delivery [21,3739]. The a2 Na+/K+ ATPase protein was barely detectable in the brain of homozygous FHM2 knockin mice and strongly reduced in the brain of heterozygous mutants [39]. FHM3 is caused by missense mutations in SCNA1A, the gene encoding the pore-forming subunit of neuronal NaV1.1 voltage-gated sodium channels [16,20]; these channels are highly expressed in particular inhibitory interneurons where they play an important role in sustaining high-frequency ring [40] (Figure 2a). Conicting ndings were obtained from the analysis of mutant recombinant human NaV1.1 channels expressed in non-neuronal cells, pointing to either gain- or loss-of-function effects of FHM3 mutations [41,42]. Given the evidence that an epilepsycausing mutation produced opposite effects on recombinant NaV1.1 channels and native NaV1.1 channels in neurons of mouse models [40], functional analysis in FHM3 mouse models appears necessary to shed light on FHM3 mechanisms. Whereas most genetic studies indicate that the FHM genes (except perhaps for ATP1A2) are not involved in
common migraines [16,21], some homozygous mutations in SLC4A4 (the gene encoding the electrogenic Na+/HCO3 cotransporter NBCe1) were recently found to be associated with either hemiplegic migraine, MA, or migraine without aura (MO), depending on the mutation [43]. Only mutations producing near total loss-of-function of the transporter expressed in glioma cells were associated with migraine, supporting a causative role and the view that hemiplegic and common migraine represent a phenotypic spectrum that may share at least some genetic basis [43] (Figure 2a). A loss-of-function frameshift mutation in KCNK18 [the gene encoding the weakly inward rectifying K+ channel (TWIK)-related spinal cord potassium channel (TRESK)], cosegregated perfectly with typical MA in a large multigenerational family [44]. TRESK channels are two-poredomain K+ channels that are broadly expressed in the nervous system, with particularly high expression in TG, where they probably play an important role in control of neuronal excitability [44]. However, a mutation leading to complete loss-of-function of the TRESK channel was recently found in both migraine and control cohorts, indicating that non-functional TRESK channels are not sufcient to cause typical migraine alone [45]. Recent genome-wide association studies have identied a few risk factors for both MA and MO that map within or near transcribed regions of interesting genes. These include metadherin (MTDH), a gene that regulates the expression of GLT-1 [46], an astrocyte glutamate transporter that plays a major role in removal of glutamate at glutamatergic synapses [47], and TRPM8 [48], a gene that encodes a cation channel expressed primarily in sensory neurons and that is involved in cold-sensing [49]. Taken together, genetic ndings suggest that migraine is a nervous system disorder characterized by altered synaptic (in particular glutamatergic) transmission and/ or altered neuronal excitability. Mechanisms of migraine headache Based on a large body of indirect evidence, it is believed that the development of migraine headache depends on the activation and sensitization of trigeminal sensory afferents
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Figure 2. Differential alteration of cortical excitatory and inhibitory synaptic transmission in FHM. (a) In FHM1, gain-of-function of presynaptic CaV2.1 channels leads to enhanced action potential-evoked glutamate release and enhanced excitatory synaptic transmission at cortical pyramidal cell (PC) synapses (left panel); inhibitory synaptic transmission at FS interneuron synapses is unaltered, despite being initiated by CaV2.1 channels (right panel) [26]. In FHM2, given the specific colocalization and functional coupling of a2 Na+/K+ pumps with glial glutamate transporters in astrocyte processes surrounding excitatory, but not inhibitory, synapses, loss-of-function of the pump might impair glutamate clearance and lead to specific gain-of-function of excitatory transmission, particularly NMDA receptor (NMDAR)-mediated transmission during high-frequency action potential (AP) trains [39]. A decreased capacity of astrocytes to buffer activity-dependent extracellular alkalosis as a consequence of loss-of-function of the Na+/HCO3 cotransporter NBCe1 has been proposed to also lead to enhanced NMDAR-mediated excitatory synaptic transmission [43]. The consequences of FHM3 mutations on NaV1.1 channels in FS interneurons, where they are highly expressed, remain unknown. (b) Schematic representation of the effect of FHM1 mutations on the specific cortical subcircuit involving recurrent excitatory synapses between PCs and reciprocal excitatory and inhibitory synapses between PCs and FS interneurons. Synaptic transmission is enhanced at excitatory synapses (as indicated by the thicker connection in the right panel compared to the left panel) but is unaltered at the inhibitory synapses in FHM1 mouse models [26]. One predicts that the gain-of-function of glutamate release at the recurrent synapses between PCs would certainly increase network excitation. By contrast, the gain-of-function of glutamate release at the synapses onto FS interneurons (PCFS synapses) would lead to enhanced recruitment of interneurons and enhanced inhibition. However, during high-frequency repetitive activity the enhanced recruitment of FS interneurons is expected to cease rapidly because the PCFS synapses have been shown to depress strongly during AP trains (much more than the recurrent PCPC synapses), and short-term depression was even stronger in FHM1 knockin mice, particularly at PCFS synapses (whereas short-term plasticity at the inhibitory FSPC synapses was unaltered) [26]. This analysis, despite being restricted to a specific subcircuit, makes the important point that the differential effects of FHM1 mutations on excitatory and inhibitory neurotransmission may produce overexcitation in certain brain conditions, but may leave the E/I balance within physiological limits in others, which is consistent with the episodic nature of the disease.
that innervate cranial tissues, in particular the meninges and their large blood vessels [57] (Figure 1a). The sensitization of mechanosensitive meningeal afferents provides a mechanism that may explain the throbbing nature of the migraine headache (typically attributed to arterial pulsation) as well as the exacerbation of the headache during events that increase intracranial pressure [50]. The primary mechanism(s) leading to activation and sensitization of the perivascular trigeminal nociceptors remain incompletely understood and controversial, particularly in the case of MO.
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Vasodilation Infusion of vasodilator substances such as CGRP or glyceril trinitrate (GTN) induce in migraineurs (but not in healthy subjects) a delayed migraine attack indistinguishable from the spontaneous attacks [51]. However, there is growing evidence that vasodilation of meningeal and/or extracranial arteries is neither necessary nor sufcient to cause migraine pain in most patients [52]. In contrast to a previous study showing lack of signicant dilatation of extracranial and intracranial arteries during GTNinduced migraine [53], a 912% dilatation of extracranial
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and intracranial arteries was recently measured in CGRPinduced migraine; this modest vasodilation is probably insufcient to activate the perivascular afferents but might affect sensitized nociceptors [54]. Meningeal inammation Based on a large body of indirect evidence from both clinical and animal studies, sterile meningeal inammation is considered to be a key mechanism that may activate and sensitize perivascular meningeal afferents and lead to migraine pain [7,55,56]. Indirect clinical evidence is provided by the increased level of various inammatory mediators in the cephalic venous outow during spontaneous migraine attacks and by the efcacy of nonsteroidal antiinammatory drugs in the acute treatment of migraine in many patients [7,55,56]. In experimental animals, activation of meningeal nociceptors in vivo leads to release of vasoactive proinammatory peptides (such as CGRP and substance P) from their peripheral nerve endings. These peptides result in vasodilation of meningeal blood vessels (mainly due to CGRP), plasma extravasation, and local activation of dural mast cells (MCs), with ensuing release of cytokines and other inammatory mediators (resulting in neurogenic inammation, NI) [5,7]. The dural trigeminal afferents exhibit properties characteristic of nociceptors in other tissues, including chemosensitivity and sensitization [7,31,50,57,58]. In vivo, most dural afferents were activated and sensitized by an inammatory soup (IF) applied to the dura; nearly all IF-sensitive dural afferents were mechanosensitive and their mechanosensitivity was enhanced by IF [59]. Chemical inammation of the dura produced facial and hind-paw cutaneous allodynia in awake behaving animals [60], with a time-course of development that is consistent with that seen in migraine patients [61]. The pharmacology of the IF-induced allodynia in animals shows important parallels with the clinical pharmacology of migraine pain [60]. Further support to the inammation hypothesis is provided by the evidence that dural MC degranulation per se can produce a long-lasting activation and sensitization of rat dural nociceptors [62], as well as cephalic tactile hypersensitivity [63]. However, the endogenous processes that promote meningeal inammation and peripheral sensitization during migraine attacks remain incompletely understood. Many investigators consider the NI produced by release of vasoactive proinammatory neuropeptides following activation of peptidergic meningeal nociceptors (by CSD or other different primary mechanisms; next section) as the endogenous inammatory process that sustains the activation and causes the long-lasting sensitization of meningeal nociceptors in many migraine attacks. Indeed, measurements of CGRP levels in the external and internal jugular venous blood have provided evidence that CGRP is released during migraine attacks [6466]. Consistent with the NI hypothesis is also the recent evidence that the headache-triggering substances ethanol and umbellolone (the major volatile constituent of the Californian headache tree) both activate peptidergic meningeal trigeminal afferents, causing CGRP release and neurogenic dura inammatory responses in experimental animals [67,68]. However, direct evidence that the release of inammatory
molecules associated with NI is able to sensitize meningeal nociceptors is lacking. In certain types of migraine, endogenous processes different from NI, and not requiring initial activation of meningeal nociceptors, might promote meningeal inammation and cause sensitization, ensuing long-lasting activation of meningeal nociceptors. These processes may include direct activation of dural MCs by several exogenous and endogenous migraine triggers, as was shown to occur in vitro [7,56,69]. They may also include the release of inammatory mediators from brain parenchyma (e.g., as a consequence of CSD) and/or from meningeal blood vessels or immune cells, which might directly sensitize meningeal nociceptors. Central sensitization After headache onset, about two-thirds of migraine patients develop cutaneous allodynia in the periorbital region that may spread to extracephalic regions [70,71]. Clinical observations and animal studies support the idea that facial allodynia reects sensitization of trigeminovascular neurons in the trigeminocervical complex (TCC) which receive convergent input from the meningeal nociceptors and facial skin [5,70,72]. Extracephalic allodynia reects sensitization of trigeminovascular thalamic neurons that process converging sensory information from the cranial meninges and extracephalic skin [5,70,73]. Moreover, these studies are consistent with the idea that initiation, but not maintenance, of central sensitization depends on the afferent input from sensitized meningeal nociceptors [5,61,70,72]. A recent study in rats points to the activation of the descending facilitatory pathway arising from the rostral ventromedial medulla (RVM) (Figure 1b) as a key central mechanism involved in IF-induced central sensitization of trigeminovascular neurons [60]. Functional magnetic resonance imaging (fMRI) studies in human subjects indicate that the periacqueductal grey (PAG) and nucleus cuneiformis (NCF), the major sources of input to the RVM (Figure 1b), are involved in central sensitization in humans [74] and that the NCF is hypofunctional in migraine patients [75]. Interestingly, positron emission tomography (PET) studies revealed activation of similar areas in the dorsal rostral brainstem during migraine attacks [76]. CGRP Several ndings support a pivotal role of CGRP in migraine, including (i) the effectiveness of CGRP receptor antagonists in migraine treatment [77,78] and (ii) the induction of a delayed migraine-like headache by intravenous CGRP administration in a large fraction of migraine patients but not in controls [79], suggesting that most migraineurs are hypersensitive to CGRP-mediated modulation of nociceptive pathways. However, the mechanisms underlying this hypersensitivity, the mechanisms of action of CGRP during a migraine attack, and the exact sites of action of CGRP receptor antagonists remain unclear and controversial [6466]. The localization of CGRP receptors in the trigeminovascular system points to multiple possible mechanisms at both peripheral and central sites [80].
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In the periphery, CGRP receptors are expressed in blood vessels, Schwann cells and dural MCs at the meninges and in glial satellite cells and a subpopulation of TG neurons in the TG [80,81]. A relevant role of CGRP-induced dural vasodilation in migraine is unlikely in view of the evidence that topical or systemic CGRP does not activate or sensitize rat dural afferents [82] and the evidence that vasodilation is neither necessary nor sufcient to trigger migraine [52]. CGRP-induced dural MC degranulation might contribute to maintaining an inammatory cycle at the dura. Consistent with this idea are animal studies showing that dural MC degranulation (as well as topical application of some individual MC mediators to the dura) preferentially activate and sensitize mechanosensitive C units, most of which express CGRP [62,83], and increase CGRP release from capsaicin-sensitive dural afferents [84]. The facilitation of CGRP-induced dural vasodilation and/or MC degranulation does not seem to contribute to headache generation in FHM1 because depolarizationevoked CGRP release from the dura was unaltered in FHM1 knockin mice [31]. It has been suggested that CGRP-mediated intraganglionic crosstalk between neurons and satellite glial cells, may promote and maintain a neuron-glia inammatory cycle, that may contribute to persistent peripheral trigeminal sensitization [64,66]. This suggestion is mainly based on the evidence that prolonged application of CGRP to cultures of TG neurons and/or satellite glial cells leads to increased gene expression and/or membrane targeting of specic receptors (e.g., P2X3) in neurons and to increased expression of inammatory genes and release of inammatory mediators from satellite glial cells; these inammatory mediators can sensitize TG neurons and act back on glial cells further activating them [8590]. It remains unclear whether similar phenomena indeed occur within the TG upon prolonged activation of meningeal nociceptors in vivo. If they do, they might be facilitated in FHM1, as suggested by ndings in TG neurons of FHM1 knockin mice, that show enhanced P2X3 receptor activity [91] and enhanced CGRP release from intact trigeminal ganglia and/or cultured neurons [31,90]. Moreover, there is some evidence that facilitation of CGRP-mediated neuron to glia crosstalk may occur in cultured TG neurons from FHM1 knockin mice following exposure to proinammatory stimuli [90]. Within the central trigeminovascular system, expression of CGRP receptors has been shown in the trigeminal nucleus caudalis (TNC, laminae III, in a ber network forming irregular glomeruli-like structures but not in second-order neurons) [80], and in some neuronal cell bodies in the ventroposteromedial (VPM) nucleus of the thalamus [92] (Figure 1a). Functional studies indicate that activation of TNC presynaptic CGRP receptors may lead to potentiation of excitatory neurotransmission [93,94]. The possibility of central mechanisms of CGRP action during a migraine attack is indirectly supported by animal studies showing that systemic CGRP does not activate or sensitize dural afferents [82]. Furthermore, high doses of systemic CGRP receptor antagonists reduce the activity of TNC neurons [95] and VPM thalamic neurons [92] evoked by stimulation of dural afferents, as well as the number of
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Fos-positive neurons in TNC (laminae III) after intravenous infusion of capsaicin [96]. However, given the very poor permeability of the bloodbrain barrier to CGRP [97,98], it seems difcult to explain how CGRP infusion can cause a migraine attack if one excludes a peripheral role of CGRP. Dysfunctional central control of pain Direct evidence in the clinical setting for increased activity of trigeminal neurons during migraine is lacking and a consistent cephalic pathology has not been detected. Therefore, some investigators propose the alternative view that migraine headache arises from dysfunction within subcortical brainstem and diencephalic nuclei that modulate trigeminal nociceptive inputs (Figure 1b). Dysfunction in these nuclei (in particular in the PAGRVM circuitry) would lead to abnormal central interpretation of normal sensory input in the trigeminovascular system, causing normal sensory trafc from the meninges to be perceived as migraine pain [99,100]. Functional imaging studies showing increased cerebral blood ow in the dorsal rostral brainstem and in the hypothalamus during migraine attacks [76,101] are considered to provide indirect support for this view [99]. However, it appears more likely that these brainstem areas function as migraine headache modulators rather than generators because their activation does not seem specic for migraine pain [101,102]. Moreover, a recent fMRI study showed activation of dorsal rostral brainstem areas only during the migraine attack and not during the preictal phase [103]. Dysfunction in brainstem nuclei involved in central control of pain and central sensitization [75,104] may lead to hyperexcitability of central trigeminovascular pathways and contribute to the development of migraine headache. Evidence from clinical and animal studies that questions the notion that abnormalities in the PAGRVM circuitry (or other descending mechanisms of pain inhibition) can generate migraine headache in the absence of peripheral sensory input has been discussed in recent reviews [6,7]. Photophobia A large fraction of migraineurs experience exacerbation of headache by light (i.e., photophobia). A neural mechanism for migraine photophobia has been recently uncovered [105]. It has been shown that dura-sensitive thalamic neurons in the rat posterior thalamus receive monosynaptic input from retinal ganglion cells (mainly intrinsically photosensitive cells involved in non-image-forming functions) and that light enhances the activity of dura-sensitive thalamic neurons located in the same area (Figure 3). The idea that a non-image-forming retinal pathway is involved in migraine photophobia is supported by the nding that exacerbation of headache by light was preserved in blind migraineurs who could sense light in the face of severe degeneration of rod and cone photoreceptors [105]. Primary brain dysfunctions in migraine The nature and mechanisms of the primary brain dysfunction(s) leading to episodic activation of the trigeminovascular pain pathway remain incompletely understood and controversial. Given the wide genetic and clinical
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Figure 3. A neural mechanism for exacerbation of migraine headache by light. (a) Extracellular single-unit electrophysiological recordings in deeply anesthetized rats revealed 20 neurons in the posterior thalamus that responded to stimulation of the dura, 14 of which were also photosensitive [105]. On average, dura-sensitive neurons increased their mean firing rate about twofold in response to ambient fluorescence light (500 lux) and fourfold in response to bright light (50000 lux), By contrast, thalamic neurons unresponsive to stimulation of the dura were also unresponsive to light. (b) Histological analysis of the recording sites indicated that most dura/light-sensitive neurons were localized at or above the dorsal border of the posterior thalamic nuclear group. Adapted, with permission, from [105]. LDVL, laterodorsal thalamic nucleus, ventrolateral; LPMR, LPLR, LPMC and LPLC, lateral posterior thalamic nuclei, mediorostral, laterorostral, mediocaudal and laterocaudal respectively; Po, posterior thalamic nuclear group; VPM, ventral posteromedial thalamic nucleus; VPL, ventral posterolateral thalamic nucleus; PLi, posterior limitans thalamic nucleus; PoT, posterior thalamic nuclear group, triangular; APT, anterior pretectal nucleus.
heterogeneity of the disorder, different primary mechanisms of migraine onset probably exist. CSD Increasing evidence from animal studies support the idea that CSD, the underlying mechanism of aura, can activate trigeminal nociception and thus trigger the headache mechanisms. A direct nociceptive effect of CSD has been demonstrated by the nding that a single CSD can lead to a long-lasting increase in ongoing activity of dural nociceptors and central trigeminovascular neurons in supercial and deep laminae of the TCC [106,107]. In most neurons, activation occurred with a delay consistent with that between the onset of visual aura and the onset of headache; the delay as well as the magnitude and duration of neuronal activation were similar in peripheral and central neurons, suggesting that CSD-evoked activity of meningeal nociceptors is sufcient to activate the central neurons. Immediate neuronal activation by CSD was observed in a fraction of neurons, mainly C nociceptors and exclusively laminae I, II TCC neurons. This suggests that it might be mediated by peptidergic nociceptors with axon collaterals extending to the pia, where immediate activation could be mediated by increased K+ or other noxious mediators released in the wake of the CSD wave. This hypothesis is supported by the demonstration that CSD-induced CGRP release from perivascular trigeminal bers contributes to the transient dilation of pial vessels measured during CSD [108]. The mechanism of the long-lasting and, in most neurons, delayed neuronal activation remains unknown. One possibility is that release of proinammatory neuropeptides in the dura promotes NI that sustains the activation of meningeal nociceptors and leads to their sensitization [7,106,107,109]. This idea is supported by the nding of CSD-induced plasma protein extravasation from dural blood vessels, which was abolished by trigeminal
nerve section [109] (but see [63,110]). Different mechanisms that may potentially explain the delayed activation of dural afferents are discussed in [63]. The CSD-induced activation of central TCC neurons might be further modulated via direct cortexTCC connections, because it has been shown that the reduction of cortical activity in primary somatosensory and insular cortical areas following CSD results in reduced and enhanced responses of TCC neurons to noxious electrical stimulation of the dura, respectively [111]. Possibly, this top-down modulation of meningeal nociception may help to explain why some people experience migraine aura without headache. In general, it remains unclear whether the activation of the trigeminovascular system induced by a CSD is sufcient to elicit the perception of headache in patients. It has been suggested that it may not be sufcient on the basis of the observation that freely moving rats do not seem to experience CSD as being aversive because they do not show pain behavior [112,113] or cutaneous allodynia [114] after a CSD (but see [115]). The idea that CSD may trigger the headache mechanisms is indirectly supported by the nding that the electrical stimulation threshold for induction of CSD in the rat cortex increases after chronic treatment with ve different migraine prophylactic drugs that are equally effective in reducing the frequency of MA and MO attacks [116]. Moreover, two drugs ineffective in migraine prophylaxis did not affect susceptibility to experimental CSD [116,117]. However, this correlation between inhibition of CSD and effectiveness in migraine prophylaxis does not appear to hold for two other drugs (although larger clinical trials appear necessary for a denite conclusion) [118,119]. The analysis of experimental CSD in FHM knockin mouse models has strengthened the view of CSD as a key migraine trigger by demonstrating that both FHM1 and FHM2 knockin mice show a lower electrical stimulation threshold for CSD induction and a higher velocity of
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Figure 4. FHM mutations facilitate the induction and the propagation of CSD. (a) The analysis of the threshold for initiation and the rate of propagation of CSD, induced in anesthetized mice by electrical stimulation of the visual cortex through a bipolar electrode, revealed a lower electrical stimulation threshold and a higher rate of propagation in both FHM1 and FHM2 knockin mice compared with wild-type (WT) mice [27,28,39]. Panel (i) shows the location of the stimulating and recording electrodes and representative CSD recordings at sites 1 and 2 in WT and homozygous FHM1 knockin (KI) mice carrying the R192Q mutation; stimulation current pulses of increasing intensity were applied at 5 min interval until a CSD was observed (the charge delivered with the first stimulation eliciting a CSD was taken as the CSD threshold). (ii) A lower CSD threshold and a higher rate of CSD propagation were measured in KI mice carrying two different human FHM1 mutations (R192Q, causing typical FHM attacks, or S218L, causing a severe hemiplegic migraine syndrome that is associated with ataxia, seizures, coma and severe brain edema often triggered by only a mild head trauma) [27,28]. S218L KI mice showed both a lower threshold for CSD induction and a faster rate of CSD propagation compared with R192Q KI mice. The facilitation of CSD was also demonstrated to be dosage-dependent, with more significant differences observed in mice homozygous for the S218L KI compared with heterozygotes. (iii) Similar findings were observed in KI mice carrying the human FHM2 mutation W887R [39]. Adapted, with permission, from [27] (i), [28] (ii) and [39] (iii). (b) The facilitation of induction and propagation of CSD in acute slices of somatosensory cortex of R192Q KI mice was completely eliminated when glutamate release at pyramidal cell synapses was reduced to WT values using a subsaturating concentration of the specific P/Q channel blocker v-AgaIVA (Aga) [26]. (i) Pressure-ejection pulses of high KCl of increasing duration were applied at 8 min interval through a glass micropipette on layer 2/3 of acute slices of somatosensory cortex until a CSD was recorded in a pyramidal cell at 600 mm from the pressure-ejection pipette; the duration of the first pulse eliciting a CSD was taken as the CSD threshold, and the rate of horizontal spread of the change in intrinsic optical signal as the velocity of CSD propagation. Similarly to observations made in vivo, the CSD threshold was lower (ii) and the CSD rate of propagation was higher (iii) in KI compared to WT mice. After perfusion of slices from KI mice with 40 nM Aga [a concentration that reduced the evoked EPSC recorded from KI pyramidal cells in microculture to the average value recorded from WT pyramidal cells, as shown by the representative traces in (iv)], the CSD threshold increased (ii) and the CSD velocity decreased (iii) to values strikingly similar to those measured in WT slices. Adapted, with permission, from [26].
CSD propagation [27,28,39] (Figure 4a). In FHM1 knockin mice carrying the mild R192Q or the severe S218L mutation, the strength of CSD facilitation as well as the severity of the post-CSD neurological motor decits and the propensity of CSD to propagate into subcortical structures were all in good correlation with the strength of the gain-offunction of the CaV2.1 channel and the severity of the clinical phenotype produced by the two FHM1 mutations [27,28,120122]. The velocity of propagation and the frequency of CSDs, elicited by continuous epidural high KCl application, were larger in female than in male FHM1 mouse mutants, in agreement with the higher female prevalence of migraine; the sex difference was abrogated by ovariectomy and enhanced by orchidectomy, suggesting that female and male gonadal hormones exert reciprocal effects [121,123]. However, no gender differences in the
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electrical threshold for CSD induction and the velocity of CSD propagation were found in FHM2 knockin mice [39]. Although FHM3 mouse models are not available, the report that FHM3 in two unrelated families cosegregates with a new eye phenotype with clinical features similar to experimental spreading depression in retina [124] suggests that, probably, the ability to facilitate CSD is also shared by FHM3 mutations. Moreover, a lower electrical threshold for CSD induction and increased velocity of CSD propagation were measured in a mouse model of cerebral autosomal dominant arteriopathy, a systemic vasculopathy associated with 5-fold increased incidence of MA [125]. Despite the strong support provided by animal studies, the idea that CSD may initiate the headache mechanisms in migraine (particularly in MO) is not generally accepted, mainly because it seems unable to explain some clinical
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observations, in particular the lack of a xed relationship between aura and headache [5,9]. The possibility that silent CSDs (i.e., CSDs involving areas of the brain that would not generate a perceived aura) may initiate the headache mechanisms in MO is neither proven nor disproven by current evidence [5,8,126]. Another argument that has been used against the idea that CSD may initiate the headache mechanisms is based on the fact that in some patients migraine premonitory symptoms may occur up to 1224 h before the onset of the headache and aura, indicating that different brain regions are activated well before the onset of CSD [12]. In this context, it is interesting that the interictal neurophysiological abnormalities in sensory information processing, typical of MO and MA patients, are not constant but change in intensity in temporal relation to the migraine attack. In most instances, the intensity of the decit reaches the maximal value in the 1224 h before the attack (i.e., the same time when the premonitory symptoms appear) and then normalize a few hours before and/or during the attack (with the exception of decits in pain processing) [5,14,15,103,127,128]. Neurophysiological reactivity to stress, one of the most common migraine triggers, increases in the period between attacks and is maximal (and signicantly higher than in healthy subjects) 13 d before an attack [127]. These data suggest that in the brain of migraineurs some intrinsic mechanisms are at work during the pain-free interval that progressively increase the dysfunction in central information processing and increase the susceptibility to migraine triggers and the neurophysiological readiness to generate a migraine attack. It seems possible that these mechanisms may lead to both the premonitory symptoms and, above a certain threshold of cortical dysfunction and/or in response to migraine triggers, create the conditions for ignition of CSD (see below). Dysfunctional regulation of cortical excitationinhibition (E/I) balance and sensory information processing The analysis of interictal cortical excitability using psychophysical, electrophysiological, transcranial magnetic stimulation (TMS) and fMRI has produced contradictory ndings and interpretations regarding the mechanisms underlying the abnormal processing of sensory information (including trigeminal nociception) in migraineurs. It is beyond the scope of the present review to discuss in detail this very large and controversial literature ([5,14,15] for reviews, and e.g., [129133] for some recent studies). Depending on the study, it has been concluded that either the cortex of migraineurs is hyperexcitable as a consequence of either enhanced excitation or reduced inhibition, or that it is hypoexcitable and/or has a lower preactivation level possibly due to serotonin hypoactivity and/or inefcient thalamo-cortical drive. Methodological problems, heterogeneity of the subjects and/or the time period relative to the last and next migraine attack, and a lack of detailed understanding of the underlying mechanisms involved in central information processing, probably account for the contradictory ndings and interpretations. Interestingly, recent TMS studies in MA patients point to decient regulatory mechanisms of cortical excitability
and ensuing reduced ability to dynamically maintain the cortical E/I balance and to prevent excessive increases in cortical excitation rather than merely hypo- or hyperexcitability as the mechanisms that underlie abnormal sensory processing [134136]. The molecular and cellular mechanisms underlying the abnormal regulation of cortical function and its periodicity remain largely unknown. The extent to which some of the cortical and/or subcortical alterations are affected by disease duration (e.g., repetitive CSDs) is also unclear. Equally unclear is the extent to which the abnormal processing of trigeminal nociceptive input reects a primary dysregulation of central sensory processing or central sensitization persisting outside the attack (e.g., [104,137]). The functional analysis of FHM knockin mouse models supports the view of migraine as a disorder of brain excitability characterized by decient regulation of the cortical E/I balance, and gives insights into the possible underlying molecular and cellular mechanisms and their relationship to CSD susceptibility. It has been shown that the gain-of-function of glutamate release at synapses onto cortical pyramidal cells can explain the facilitation of experimental CSD in FHM1 knockin mice [26] (Figure 4b). The data are consistent with, and support a model of, CSD initiation in which CaV2.1-dependent release of glutamate from cortical pyramidal cell synapses and activation of NMDA receptors (and possibly postsynaptic CaV2.1 channels) play a key role in the positive feedback cycle that ignites CSD [26,138,139]. The demonstration that FHM1 mutations may differently affect synaptic transmission and short-term plasticity at cortical excitatory and inhibitory synapses (noting the lack of effect at FS interneuron synapses) [26] implies that, very probably, the FHM1 mutations alter the neuronal circuits that dynamically adjust the E/I balance during cortical activity [140,141] (Figure 2b). It seems plausible to hypothesize that these alterations may in certain conditions lead to disruption of the E/I balance, overexcitation (due to excessive recurrent excitatory activity) and neuronal hyperactivity, that may create conditions for the initiation of spontaneous CSDs (e.g., by increasing the extracellular [K+] above a critical value). Similar mechanisms might underlie the susceptibility to CSD in FHM2, given that loss-of-function of the a2 Na+/K+ ATPase might impair glutamate clearance and mainly affect excitatory synaptic transmission [39] (Figure 2a). Thus, ndings from FHM mouse models suggest that impairment of the cortical circuits that dynamically adjust the E/I balance during cortical activity, due to excessive recurrent glutamatergic neurotransmission, may underlie both the abnormal regulation of cortical function and the susceptibility to CSD in FHM (Figure 5). It is certainly possible that FHM mutations produce parallel dysfunctions in subcortical areas that might also contribute to the altered regulation of cortical function and in general to the disease in a way that remains to be established (e.g., by altering cortical neuromodulation by monoaminergic projections and/or by favoring hyperexcitability of central trigeminovascular pathways). In this context, CSD might represent only one manifestation of fundamental
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Figure 5. Proposed pathophysiological mechanisms in the generation of migraine. It is proposed that migraine is a disorder of brain excitability characterized by deficient regulation of the E/I balance during cortical (and possibly subcortical) activity. In FHM(1,2) and possibly some other migraine subtypes (large blue arrow pathways), excessive recurrent glutamatergic neurotransmission in the cortex (pink boxes) is proposed to lead to alterations in the cortical circuits that dynamically adjust the cortical E/I balance. This results in dysfunctional sensory processing and, under certain conditions (e.g., migraine triggers), in disruption of the E/I balance and neuronal hyperactivity, which creates conditions for ignition of CSD and consequent generation of aura and activation of the trigeminovascular pain pathway. Given the wide clinical and genetic heterogeneity of migraine, different molecular and cellular mechanisms that remain to be elucidated may underlie the impaired regulation of cortical function and the susceptibility to CSD in different migraine subtypes (as indicated by the parallel thin blue arrow pathways). The proposed scheme also includes the possibility that, in both FHM and common migraine, dysfunctions in subcortical areas (green box) might contribute to the altered regulation of cortical function and to the development of migraine headache (e.g., by leading to hyperexcitability of central trigeminovascular pathways).
alterations (e.g., impairment of E/I balance) produced by FHM mutations in different brain areas (Figure 5). Similar mechanisms may underlie the abnormal regulation of cortical (and possibly subcortical) function in some common migraine subtypes, for which there is indirect evidence consistent with enhanced cortical glutamatergic neurotransmission [46,136,142] and enhanced cortico-cortical or recurrent excitatory neurotransmission [129,130,132,135]. Given the wide clinical and genetic heterogeneity of migraine, different molecular and cellular mechanisms may well underlie the impaired regulation of brain function and the susceptibility to CSD in different migraineurs (parallel arrows in Figure 5). Despite recent drug developments, there is a great need for more efcacious and specic prophylactic migraine medications [143]. The recent advances in our understanding of migraine primary brain dysfunctions support novel therapeutic strategies that consider cortical E/I dysregulation and CSD as key targets of preventive migraine treatment. In particular, cortical glutamatergic synapses appear as key therapeutic targets for novel drugs aimed at counteracting excessive glutamatergic synaptic transmission in FHM and some migraine subtypes. Particularly efcacious would be drugs that increase CSD threshold independently of the specic cortical dysfunctions underlying susceptibility to CSD in different migraineurs.
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Concluding remarks Taken together, currently available evidence suggests that migraine is a disorder of brain excitability characterized by decient regulation of the E/I balance during cortical activity. The mechanisms underlying the decient regulation of the cortical E/I balance might lead to both (i) the typical interictal dysfunction in sensory (including trigeminal nociceptive) information processing, that progressively increases in the period between attacks, and (ii) in particular conditions, ignition of CSD and activation of the trigeminovascular pain pathway. To verify this hypothesis, future studies should investigate the molecular and cellular mechanisms underlying cortical E/I balance dysregulation and the susceptibility to CSD in migraine, in addition to how migraine triggers modulate these mechanisms. Future research should also elucidate how the cortical and/or subcortical dyfunctions lead to activation and sensitization of the trigeminovascular pain pathway (Box 1). Functional studies in genetic mouse models have begun to unravel the molecular and cellular mechanisms underlying the dysfunctional regulation of the cortical E/I balance and the susceptibility to CSD in FHM. These mechanisms remain largely unknown for the common forms of migraine, for which the discovery of causative genes is a key aspect of future research efforts (Box 1). Better knowledge of the mechanisms of initiation and
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Box 1. Outstanding questions
Genetics: which genes are involved in common migraine(s) and how do they cooperate in causing the disease? What are the identities of the FHM genes that remain to be identified? Primary brain dysfunctions: although it is clear that most migraine attacks start in the brain, a major general outstanding question concerns the nature and mechanisms of the primary brain dysfunctions that cause episodic activation of the trigeminovascular pain pathway. To understand the primary brain mechanisms of migraine it seems essential that future studies address the following specific questions: (i) How are the cortical circuits that dynamically adjust the E/I balance specifically altered in FHM mouse models, and in which conditions may these alterations lead to disruption of the E/I balance in a way that allows CSD ignition? (ii) What are the molecular and cellular mechanisms underlying the dysfunctional regulation of the cortical E/I balance and the abnormal processing of sensory information, and its periodicity, in migraineurs? How are they affected by migraine triggers and by repeated attacks? (iii) Do silent CSDs occur in MO and what are the underlying molecular and cellular mechanisms? Mechanisms of activation and sensitization of the trigeminovascular pain pathway: it is generally recognized that the throbbing migraine headache is due to long-lasting sensitization of meningeal trigeminovascular nociceptors (peripheral sensitization) together with, in most patients, central sensitization of the trigeminovascular pain pathway. A major general outstanding question is how the migraine primary brain dysfunctions lead to activation and sensitization of the trigeminovascular pathway. Specic questions to address are: (i) What are the mechanisms of the sustained, and in most cases, delayed activation of dural trigeminal afferents induced by CSD in animal studies? Is NI involved? More generally, is NI the endogenous process underlying peripheral sensitization of meningeal nociceptors? Is a neuronglia inflammatory cycle at the TG level involved? If other mechanisms are involved, what is their nature? (ii) Are subcortical and/or cortical structures that are involved in the central control of pain dysfunctional in migraine? What are the molecular and cellular mechanisms of their specific dysfunctions?
University of Padova (Strategic Project: Physiopathology of Signaling in Neuronal Tissue) and Fondazione Cariparo (Excellence Project: Calcium Signaling in Health and Disease) and acknowledges the support from Telethon-Italy (GGP06234).
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propagation of CSD and of CSD facilitation in mouse genetic models will help the development of novel prophylactic migraine medications. The understanding of the molecular and cellular mechanisms underlying cortical E/I balance dysregulation in different migraine forms will be essential for the development of novel prophylactic medications tailored to distinct therapeutic targets in different patients. Note added in proof As this review went to press, Freilinger et al. [146] published the ndings of the rst genome-wide association study of migraine without aura (MO). One of the susceptibility loci for MO identied in this study appears particularly interesting, since it is within the MEF2D gene that encodes a transcription factor that mediates neuronal activity-dependent transcription in neurons and plays a key role in many aspects of synapse and neural circuit development and function [147].
Acknowledgments
We would like to apologize to the many investigators whose work we were unable to cite due to space limitations. D.P. is supported by grants from
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Migraine: a disorder of brain excitatoryinhibitory balance?

Trends in Neurosciences August 2012, Vol. 35, No. 8

Efferent modulatory pathways

Dura mater Pia mater Cerebral cortex

SSN TG RVM TG RVM

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Trends in Neurosciences August 2012, Vol. 35, No. 8

Inhibitory FS interneuron synapse FHM3

GluR NMDAR FHM2 (b) 2 ATPase Na+,K+

Trends in Neurosciences August 2012, Vol. 35, No. 8

Trends in Neurosciences August 2012, Vol. 35, No. 8

Trends in Neurosciences August 2012, Vol. 35, No. 8

3.60 LPMR LDVL

LPMC LPLC APT LPMR Po VPM

Dura/light sensitive (n = 14) Dura sensitive (n = 6) Dura/light insensitive (n = 14)

LPMC LPLC APT PLi PoT

Trends in Neurosciences August 2012, Vol. 35, No. 8

CSD in FHM1 knockin mice in vivo

CSD in FHM2 knockin mice in vivo

Evoked EPSC ***

CSD velocity (mm/min)

CSD threshold (ms)

2.5 2.0 1.5 1.0 0.5

20 0 V (mV) -20 -40 -60 -80

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Trends in Neurosciences August 2012, Vol. 35, No. 8

Migraine triggers Cortical E/I unbalance

Activation, sensitization of the trigeminovascular pain pathway

Trends in Neurosciences August 2012, Vol. 35, No. 8

Trends in Neurosciences August 2012, Vol. 35, No. 8

Trends in Neurosciences August 2012, Vol. 35, No. 8

Trends in Neurosciences August 2012, Vol. 35, No. 8

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