Excitatory Inhibitory Balance

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  • 8/12/2019 Excitatory Inhibitory Balance


    Feature Review

    Migraine: a disorder of brainexcitatoryinhibitory balance?Dania Vecchia 1 and Daniela Pietrobon 1 , 2

    1 Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy2 CNR Institute of Neuroscience, 35121 Padova, Italy

    Migraine is a common disabling brain disorder whosekey manifestations are recurrent attacks of unilateralheadache and interictal hypersensitivity to sensory sti-muli. Migraine arises from a primary brain dysfunctionthat leads to episodic activation and sensitization of thetrigeminovascular pain pathway and as a consequence








    molecularand cellular mechanisms of the primary brain dysfunc-tion(s) and of migraine pain. We review here our currentunderstanding of these mechanisms, focusing on recentadvances regarding migraine genetics, headache mech-anisms, and the primary brain dysfunction(s) underlyingmigraine onset and susceptibility to cortical spreadingdepression, the neurophysiological correlate of migraineaura. We also discuss insights obtained from the func-tional analysis of familial hemiplegic migraine mousemodels.

    IntroductionMigraine is a common episodic neurological disorder withcomplex pathophysiology that manifests itself as recurrentattacks of typically throbbing and unilateral, often severe,headache with associated features such as nausea, phono-phobia and/or photophobia; in a third of patients the head-ache is preceded by transient neurological symptoms thatare most frequently visual but may involve other senses(migraine with aura: MA) [1] (Table 1 ). Migraine is a publichealth problem of great impact upon boththe individual andsociety. It is one of the 20 most disabling diseases (according to World Health Organization ranking [2]). Furthermore, itis remarkably common (e.g., it affects 17% of femalesand 8%of males in the European population [3]) and very costly (EUR 18.5 billion/year in Europe [4]).








    dependson the activation and sensitization of the trigeminovascu-lar pain pathway [57] (Figure 1 ), and that cortical spread-ing depression (CSD)-like events underlie migraine aura[5,8,9] . CSD can be induced in animals by focal stimulationof the cerebral cortex and consists of a slowly propagating (26 mm/min) wave of strong neuronal and glial depolari-zation whose mechanisms of initiation and propagationremain unclear [10,11] . It is also generally recognized thatmost migraine attacks start in the brain. This is suggestedby the premonitory symptoms (such as difculty with

    speech and reading, increased emotionality, sensory hypersensitivity) which in many patients are highly predictive of the attack although occurring up to 12 hbefore it [12] as well as by the nature of some typicalmigraine triggers (e.g., stress, sleep deprivation, oversleep-ing, hunger and/or prolonged sensory stimulation) [13] .






    pro- vided clear evidence that in the period between attacksmigraineurs show hypersensitivity to sensory stimuli andabnormal processing of sensory information, characterizedby increased amplitudes and reduced habituation of evoked and event-related potentials [14,15] .

    The nature and mechanisms of the primary brain dys-function(s) leading to the onset of a migraine attack, toCSD susceptibility, and to episodic activation of the trige-minovascular pain pathway remain largely unknown andare major outstanding issues to be addressed in furthering our understanding of the neurobiology of migraine. Otherimportant open questions concern the mechanisms of mi-graine pain.

    Here, we review recent advances regarding (i) the ge-netics of migraine; (ii) the mechanisms of migraine head-ache, focusing on the roles of meningeal inammation,calcitonin gene-related peptide (CGRP), central sensitiza-tion, and dysfunctional central control of pain; and (iii) themechanisms of the primary brain dysfunction(s) leading toepisodic activation of the trigeminovascular pain pathway.We also discuss insights into these mechanisms obtainedfrom the functional analysis of mouse models of familialhemiplegic migraine (FHM), a rare monogenic autosomaldominant form of MA.

    Genetics of migraine








    heritability estimates as high as 50% and probable polygenic multifac-torial inheritance [16,17] . The complexity of the diseasehas hampered the identication of common susceptibility variants; the lack of consensus on most of the identiedsusceptibility loci probably reects clinical and geneticheterogeneity [16,17] .

    Most of our current understanding of genetic factorsunderlying migraine comes from studies of FHM. Threecausative genes, all encoding ion channels or transporters,have been identied [16,1821] . Additional FHM genescertainly exist and remain to be identied [22] . Apart fromthe motor weakness or hemiparesis during aura, typicalFHM attacks resemble MA attacks (Table 1 ) and both


    Corresponding author: Pietrobon, D. ( daniela.pietrobon@unipd.it ). Keywords: migraine; trigeminovascular pain; spreading depression; excitatoryinhibitory balance; channelopathy..

    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. 8 507

  • 8/12/2019 Excitatory Inhibitory Balance


    types of attacks may alternate in patients and co-occurwithin families, suggesting that FHM and MA may be partof the same spectrum and may share some pathogeneticmechanisms. Some FHM patients can also have atypicalsevere attacks and/or permanent cerebellar symptoms[16,21] .

    FHM1 is caused by missense mutations in CACNA1A ,the gene encoding the pore-forming subunit of neuronalCa V 2.1 (P/Q-type) voltage-gated calcium channels [18,23] .These calcium channels are widely expressed in the ner- vous system, including all brain regions implicated in thepathogenesis of migraine. Ca V 2.1 channels play a domi-nant role in controlling neurotransmitter release, particu-larly at central synapses. Their somatodendriticlocalization points to additional postsynaptic roles, suchas in neural excitability [23,24] .

    Analysis of the single channel properties of mutant re-combinant human Ca V 2.1 channels and of the P/Q-typecalcium current in different neurons [including corticaland trigeminal ganglion (TG) neurons] of knockin mice

    carrying FHM1 mutations revealed that the mutationsproduce gain-of-function of Ca V 2.1 channels, mainly dueto increased channel open probability and channel activa-tion at lower voltages [23,2531] . However, the gain-of-function effect may be dependent on the specic Ca V 2.1splice variant and/or auxiliary subunit [32,33] . In TG neu-rons of FHM1 knockin mice the P/Q-type calcium currentwas increased in a subtype of neuron (that does not inner- vate the dura) but was unaltered in capsaicin-sensitiveneurons innervating the dura; congruently, the FHM1 mu-tation did not alter depolarization-evoked CGRP releasefrom the dura, but increased CGRP release from trigeminalganglia [31] . In the cerebral cortex of FHM1 knockin mice,excitatory synaptic transmission was enhanced as a conse-quence of increased action potential-evoked glutamaterelease at pyramidal cell synapses; in striking contrast,inhibitory neurotransmission at fast-spiking (FS) interneu-ron synapses was unaltered (despite being initiated by P/Q-type calcium channels) [26] (Figure 2a). Neuron sub-type- and synapse-specic effects may help to explain why a

    (a) (b) Efferent modulatory pathways






    S1 Ins


    Afferent pathways

    Dura mater


    Pia mater




    S1 S2 Ins







    TRENDS in Neurosciences

    Figure 1 . Schematic illustration of important neuronalstructures and connections in the trigeminovascular pathways involvedin migraineheadache. (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 C1C2 dorsalhorns of thecervical spinalcord and thecaudal division of thespinal trigeminal nucleus (TNC) (C-fibersmainly in superficial layers; A- d fibersin deep layers). TheTCC 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 mak

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