1,721,072 research outputs found
Migraine: New molecular mechanisms
No full textMigraine 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
Calcium channels and migraine.
No full textMissense mutations in CACNA1A, the gene that encodes the pore-forming α1 subunit of human voltage-gated CaV2.1 (P/Q-type) calcium channels, cause a rare form of migraine with aura (familial hemiplegic migraine type 1: FHM1). Migraine is a common disabling brain disorder whose key manifestations are recurrent attacks of unilateral headache that may be preceded by transient neurological aura symptoms. This review, first, briefly summarizes current understanding of the pathophysiological mechanisms that are believed to underlie migraine headache, migraine aura and the onset of a migraine attack, and briefly describes the localization and function of neuronal CaV2.1 channels in the brain regions that have been implicated in migraine pathogenesis. Then, the review describes and discusses i) the functional consequences of FHM1 mutations on the biophysical properties of recombinant human CaV2.1 channels and native CaV2.1 channels in neurons of knockin mouse models carrying the mild R192Q or severe S218L mutations in the orthologous gene, and ii) the functional consequences of these mutations on neurophysiological processes in the cerebral cortex and trigeminovascular system thought to be involved in the pathophysiology of migraine, and the insights into migraine mechanisms obtained from the functional analysis of these processes in FHM1 knockin mice. This article is part of a Special Issue entitled: Calcium channels
Calcium channels and channelopathies of the central nervous system
No full textSeveral inherited human neurological disorders can be caused by mutations in genes encoding Ca2+ channel subunits. This review deals with known human and mouse calcium channelopathies of the central nervous system (CNS). The human diseases comprise: 1) a recessive retinal disorder, X-linked congenital stationary night blindness, associated with mutations in the CACNA1F gene, encoding alpha(1)1.4 subunits of L-type channels; and 2) a group of rare allelic autosomal dominant human neurological disorders including familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6, all associated with mutations in the CACNA1A gene, encoding alpha(1)2.1 subunits of P/Q-type calcium channels: Mutations at the mouse orthologue of the CACNA1A gene cause a group of recessive neurological disorders, including the tottering, leaner, and rocker phenotypes with ataxia and absence epilepsy, and the rolling Nagoya phenotype with ataxia without seizures. Two other spontaneous mouse mutants with ataxia and absence epilepsy, lethargic and stargazer, have mutations in genes encoding a calcium channel auxiliary (3 subunit and a putative calcium channel auxiliary gamma subunit. For each channelopathy, the review describes disease phenotype, channel genotype, and known functional consequences of the pathological mutations; in some cases, it also describes working hypothesis and/or speculations addressing the challenging question of how the alterations in channel function lead to selective cellular dysfunction and disease
Function and dysfunction of synaptic calcium channels: insights from mouse models
No full textIn the past few years several spontaneous or engineered mouse models with mutations in Ca2+ channel genes have become available, providing a powerful approach to defining Ca2+ channel function in vivo. There have been recent advances in outlining the phenotypes and in the functional analysis of mouse models with mutations in genes encoding the pore-forming subunits of Ca(V)2.1 (P/Q-type), Ca(V)2.2 (N-type) and Ca(V)2.3 (R-type) Ca2+ channels, the channels involved in controlling neurotransmitter release at mammalian synapses. These data indicate that Ca(V)2.1 channels have a dominant and efficient specific role in initiating fast synaptic transmission at central excitatory synapses in vivo, and suggest that the Ca(V)2.1 channelopathies are primarily synaptic diseases. The different disorders probably arise from disruption of neurotransmission in specific brain regions: the cortex in the case of migraine, the thalamus in the case of absence epilepsy and the cerebellum in the case of ataxia
CaV2.1 channelopathies
No full textMutations in the CACNA1A gene that encodes the pore-forming alpha(1) subunit of human voltage-gated Ca(V)2.1 (P/Q-type) Ca(2+) channels cause several autosomal-dominant neurologic disorders, including familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). For each channelopathy, the review describes the disease phenotype as well as the functional consequences of the disease-causing mutations on recombinant human Ca(V)2.1 channels and, in the case of FHM1 and SCA6, on neuronal Ca(V)2.1 channels expressed at the endogenous physiological level in knockin mouse models. The effects of FHM1 mutations on cortical spreading depression, the phenomenon underlying migraine aura, and on cortical excitatory and inhibitory synaptic transmission in FHM1 knockin mice are also described, and their implications for the disease mechanism discussed. Moreover, the review describes different ataxic spontaneous cacna1a mouse mutants and the important insights into the cerebellar mechanisms underlying motor dysfunction caused by mutant Ca(V)2.1 channels that were obtained from their functional characterization
Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine
No full textMigraine is a very common disabling brain disorder with unclear pathogenesis. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in Ca(V)2.1 (P/Q-type) Ca2+ channels. This review describes the functional consequences of FHM1 mutations in knockin mouse models carrying the mild R192Q or severe S218L mutations in the orthologous gene. The FHM1 knockin mice show allele dosage-dependent gain-of-function of neuronal P/Q-type Ca2+ current, reflecting activation of mutant channels at lower voltages, and allele dosage- and sex-dependent facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura. Gain-of-function of neuronal Ca2+ current, facilitation of CSD and post-CSD motor deficits were larger in S218L than R192Q knockin mice, in correlation with the more severe human S218L phenotype. Enhanced cortical excitatory neurotransmission, due to increased action potential-evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses, were demonstrated in R192Q knockin mice. Evidence for a causative link between enhanced glutamate release and CSD facilitation was obtained. The data from FHM1 mice strengthen the view of CSD as a key player in the pathogenesis of migraine, give insight into CSD mechanisms and point to episodic disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for vulnerability to CSD ignition in migraine
Familial Hemiplegic Migraine
No full textFamilial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCAA 1A, encoding the pore-forming alpha(1) subunits of the neuronal voltage-gated Ca2+ channels Ca(v)2.1 and Na+ channels Na(v)l.l, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the alpha(2) subunit of the Na+, K+ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHMI knockin mice and of several FHM mutants in heterologous expression systems (12 FHMI, 8 FHM2, and I FHM3). These studies show the following: (1) FHMI mutations produce gain-of-function of the Ca(v)2.1 channel and, as a consequence, increased Ca(v)2.1 -dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phe-omenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the zeta(2) Na+,K+-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na(v)1.5 (and presumably Na(v)1. 1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K+ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K+ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment
Lessons from Familial Hemiplegic Migraine and Cortical Spreading Depression
Full text linkMigraine is a common episodic neurological disorder with complex pathophysiology. It is generally recognized that: most migraine attacks start in the brain; migraine headache depends on the activation and sensitization of the trigeminovascular pain pathway; and cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura. Most of the current molecular understanding of migraine comes from studies of familial hemiplegic migraine (FHM), a rare monogenic autosomal dominant form of migraine with aura (MA). This chapter focuses on the physiological role of the proteins encoded by the three known FHM genes and the functional consequences of FHM mutations. It also focuses on the insights into the mechanisms underlying susceptibility to CSD and initiation of migraine attacks obtained from the functional analysis of FHM mouse models. Three different FHM mouse models have been generated by introducing the human FHM1R192Q or S218L and FHM2W887R mutations into the orthologous genes
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