Article

Migraine: New Molecular Mechanisms

Department of Biomedical Sciences, University of Padova, Padova, Italy.
The Neuroscientist (Impact Factor: 6.84). 09/2005; 11(4):373-86. DOI: 10.1177/1073858405275554
Source: PubMed

ABSTRACT

Migraine is an episodic headache disorder affecting more than 10% of the general population. Migraine arises from a primary brain dysfunction that leads to activation and sensitization of the trigeminovascular system. A major incompletely understood issue in the neurobiology of migraine concerns the molecular and cellular mechanisms that underlie the primary brain dysfunction and lead to activation and sensitization of the trigeminovascular system, thus generating and maintaining migraine pain. Here the author reviews recent discoveries that have advanced our understanding of these mechanisms toward a unifying pathophysiological hypothesis, in which cortical spreading depression (CSD), the phenomenon underlying migraine aura, assumes a key role. In particular, the author discusses the main recent findings in the genetics and neurobiology of familial hemiplegic migraine and the insights they provide into the molecular and cellular mechanisms that may lead to the increased susceptibility of CSD in migraineurs.

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Available from: Daniela Pietrobon, Nov 05, 2015
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    • "The generation of two knock-in (KI) FHM-1 mouse models carrying either the human pathogenic R192Q or S218L missense mutations allowed the first analysis of the functional consequences of FHM-1 mutations on Ca V 2.1 channels and synaptic transmission in neurons expressing the channels at the endogenous physiological level (van den Maagdenberg et al., 2010, 2007, 2004; Kaja et al., 2010; Tottene et al., 2009; Gonz alez Inchauspe et al., 2010; Adams et al., 2010). In agreement with the hypothesis that considers CSD as the underlying mechanism of the migraine aura (Lauritzen, 1994; Haerter et al., 2005; Pietrobon, 2005; Welch, 1998; Flippen and Welch, 1997), the KI mice carrying the human FHM-1 R192Q or S218L mutation exhibit a lower threshold for induction of CSD and an increased velocity of CSD propagation (van den Maagdenberg et al., 2004, 2010; Tottene et al., 2009; Eikermann-Haerter et al., 2009). Studies in KI mice revealed multiple gain-of-function effects. "
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    ABSTRACT: CaV2.1 Ca2+ channels play a key role in triggering neurotransmitter release and mediating synaptic transmission. Familial hemiplegic migraine type-1 (FHM-1) is caused by missense mutations in the CACNA1A gene that encodes the α1A pore-forming subunit of CaV2.1 Ca2+ channels. We used knock-in (KI) transgenic mice harbouring the pathogenic FHM-1 mutation R192Q to study inhibitory and excitatory neurotransmission in the principle neurons of the lateral superior olive (LSO) in the auditory brainstem. We tested if the R192Q FHM-1 mutation differentially affects excitatory and inhibitory synaptic transmission, disturbing the normal balance between excitation and inhibition in this nucleus. Whole cell patch-clamp was used to measure neurotransmitter elicited excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in wild-type (WT) and R192Q KI mice. Our results showed that the FHM-1 mutation in CaV2.1 channels has multiple effects. Evoked EPSC amplitudes were smaller whereas evoked and miniature IPSC amplitudes were larger in R192Q KI compared to WT mice. In addition, in R192Q KI mice, the release probability was enhanced compared to WT, at both inhibitory (0.53 ± 0.02 vs. 0.44 ± 0.01, P = 2.10−5, Student's t-test) and excitatory synapses (0.60 ± 0.03 vs. 0.45 ± 0.02, P = 4 10−6, Student's t-test). Vesicle pool size was diminished in R192Q KI mice compared to WT mice (68 ± 6 vs 91 ± 7, P = 0.008, inhibitory; 104 ± 13 vs 335 ± 30, P = 10−6, excitatory, Student's t-test). R192Q KI mice present enhanced short-term plasticity. Repetitive stimulation of the afferent axons caused short-term depression (STD) of E/IPSCs that recovered significantly faster in R192Q KI mice compared to WT. This supports the hypothesis of a gain-of-function of the CaV2.1 channels in R192Q KI mice, which alters the balance of excitatory/inhibitory inputs and could also have implications in the altered cortical excitability responsible for FHM pathology.
    Full-text · Article · Dec 2014 · Hearing Research
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    • "Migraines are the most common headache disorder and affect more than 10% of the general population [49,50]. Migraines are thought to arise from the activation and sensitization of the trigeminovascular system, followed by the release of inflammatory mediators from the trigeminal system, with a consequent vasodilation of innervate intracranial blood vessels and generation of neurogenic inflammation [51]. Such inflammation causes hyperexcitability of TG neurons (peripheral sensitization) and the second-order sensory neurons (central sensitization) [52,53]. "
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    ABSTRACT: Amitriptyline (AMI) is tricyclic antidepressant that has been widely used to manage various chronic pains such as migraines. Its efficacy is attributed to its blockade of voltage-gated sodium channels (VGSCs). However, the effects of AMI on the tetrodotoxin-resistant (TTX-r) sodium channel Nav1.9 currents have been unclear to present. Using a whole-cell patch clamp technique, this study showed that AMI efficiently inhibited Nav1.9 currents in a concentration-dependent manner and had an IC50 of 15.16 μM in acute isolated trigeminal ganglion (TG) neurons of the rats. 10 μM AMI significantly shifted the steady-state inactivation of Nav1.9 channels in the hyperpolarizing direction without affecting voltage-dependent activation. Surprisingly, neither 10 nor 50 μM AMI caused a use-dependent blockade of Nav1.9 currents elicited by 60 pulses at 1 Hz. These data suggest that AMI is a state-selective blocker of Nav1.9 channels in rat nociceptive trigeminal neurons, which likely contributes to the efficacy of AMI in treating various pains, including migraines.
    Full-text · Article · Jun 2013 · Molecular Pain
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    • "The AMPA receptor proteins are products of separate genes that arrange to form ligand-gated ion channels in the plasma membrane permeable to Na+, K+ and Ca2+ (45). The four domains are arranged in a tetrameric structure to form a transmembrane aqueous pore (46). Two SNPs in GRIA1 (5q33.2, "
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    ABSTRACT: Migraine is a common genetically linked neurovascular disorder. Approximately ∼12% of the Caucasian population are affected including 18% of adult women and 6% of adult men (1, 2). A notable female bias is observed in migraine prevalence studies with females affected ∼3 times more than males and is credited to differences in hormone levels arising from reproductive achievements. Migraine is extremely debilitating with wide-ranging socioeconomic impact significantly affecting people's health and quality of life. A number of neurotransmitter systems have been implicated in migraine, the most studied include the serotonergic and dopaminergic systems. Extensive genetic research has been carried out to identify genetic variants that may alter the activity of a number of genes involved in synthesis and transport of neurotransmitters of these systems. The biology of the Glutamatergic system in migraine is the least studied however there is mounting evidence that its constituents could contribute to migraine. The discovery of antagonists that selectively block glutamate receptors has enabled studies on the physiologic role of glutamate, on one hand, and opened new perspectives pertaining to the potential therapeutic applications of glutamate receptor antagonists in diverse neurologic diseases. In this brief review, we discuss the biology of the Glutamatergic system in migraine outlining recent findings that support a role for altered Glutamatergic neurotransmission from biochemical and genetic studies in the manifestation of migraine and the implications of this on migraine treatment.
    Full-text · Article · Mar 2013
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