High Cortical Spreading Depression Susceptibility and Migraine-Associated Symptoms in Ca(V)2.1 S218L Mice

Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Annals of Neurology (Impact Factor: 9.98). 08/2009; 67(1):85-98. DOI: 10.1002/ana.21815
Source: PubMed


The CACNA1A gene encodes the pore-forming subunit of neuronal Ca(V)2.1 Ca2+ channels. In patients, the S218L CACNA1A mutation causes a dramatic hemiplegic migraine syndrome that is associated with ataxia, seizures, and severe, sometimes fatal, brain edema often triggered by only a mild head trauma.
We introduced the S218L mutation into the mouse Cacna1a gene and studied the mechanisms for the S218L syndrome by analyzing the phenotypic, molecular, and electrophysiological consequences.
Cacna1a(S218L) mice faithfully mimic the associated clinical features of the human S218L syndrome. S218L neurons exhibit a gene dosage-dependent negative shift in voltage dependence of Ca(V)2.1 channel activation, resulting in enhanced neurotransmitter release at the neuromuscular junction. Cacna1a(S218L) mice also display an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus. In contrast, mice bearing the R192Q CACNA1A mutation, which in humans causes a milder form of hemiplegic migraine, typically exhibit only a single CSD event after one triggering stimulus.
The particularly low CSD threshold and the strong tendency to respond with multiple CSD events make the S218L cortex highly vulnerable to weak stimuli and may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. Thus, the S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma-triggered cerebral edema.

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Available from: Chris I De Zeeuw, Oct 07, 2015
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    • "In contrast to this study, mutant mouse models expressing human FHM type 1 mutations in the same gene (R192Q or S218L) exhibit increased susceptibility to SD in the neocortex and the transient hemiplegia in response to SD initiation(20, 33, 34). The S218L variant exhibits larger gain-of-function (in vitro) and higher SD susceptibility (in vivo) in comparison to the R192Q mutation (33, 34). In contrast to pure hemiplegic migraine associated with the R192Q mutation, attacks in patients carrying the S218L mutation are sometimes accompanied by disturbances of consciousness, such as coma or stupor, and generalized seizures (18). "
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    ABSTRACT: Objective Familial hemiplegic migraine (FHM) is an autosomal dominantly inherited subtype of migraine with aura, characterized by transient neurological signs and symptoms. Typical hemiplegic migraine attacks start in the first or second decade of life. Some patients with FHM suffer from daily recurrent attacks since childhood. Results from extensive studies of cellular and animal models have indicated that gene mutations in FHM increase neuronal excitability and reduce the threshold for spreading depression (SD). SD is a transient wave of profound neuronal and glial depolarization that slowly propagates throughout the brain tissue and is characterized by a high amplitude negative DC shift. After induction of SD, S218L mutant mice exhibited neurological signs highly reminiscent of clinical attacks in FHM type 1 patients carrying this mutation. FHM1 with ataxia is attributable to specific mutations that differ from mutations that cause pure FHM1 and have peculiar consequences on cerebellar Cav2.1 currents that lead to profound Purkinje cell dysfunction and neuronal loss with atrophy. SD in juvenile rats produced neuronal injury and death. Hormonal factors involved in FHM affect SD initiation and propagation. The data identify SD as a possible target of treatment of FHM. In addition, FHM is a useful model to explore the mechanisms of more common types of migraine.
    Iranian Journal of Child Neurology 03/2014; 8(3):6-11.
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    • "However, the fact that a sudden wave of cortical depolarization is tightly coupled to a form of headache is consistent with the idea that homeostatic mechanisms keep neuronal functions within normal physiological ranges—and more importantly, that these mechanisms could be impaired in FHM1 migraine sufferers. There exist knock-in mouse models of FHM1 (van den Maagdenberg et al., 2004, 2010). These knock-in models have been a wonderful resource to deduce P/Q-channel properties of FHM1-inducing amino acid substitutions and to establish that the substitutions do represent gains of channel function. "
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    ABSTRACT: Throughout life, animals face a variety of challenges such as developmental growth, the presence of toxins, or changes in temperature. Neuronal circuits and synapses respond to challenges by executing an array of neuroplasticity paradigms. Some paradigms allow neurons to up- or downregulate activity outputs, while countervailing ones ensure that outputs remain within appropriate physiological ranges. A growing body of evidence suggests that homeostatic synaptic plasticity (HSP) is critical in the latter case. Voltage-gated calcium channels gate forms of HSP. Presynaptically, the aggregate data show that when synapse activity is weakened, homeostatic signaling systems can act to correct impairments, in part by increasing calcium influx through presynaptic CaV2-type channels. Increased calcium influx is often accompanied by parallel increases in the size of active zones and the size of the readily releasable pool of presynaptic vesicles. These changes coincide with homeostatic enhancements of neurotransmitter release. Postsynaptically, there is a great deal of evidence that reduced network activity and loss of calcium influx through CaV1-type calcium channels also results in adaptive homeostatic signaling. Some adaptations drive presynaptic enhancements of vesicle pool size and turnover rate via retrograde signaling, as well as de novo insertion of postsynaptic neurotransmitter receptors. Enhanced calcium influx through CaV1 after network activation or single cell stimulation can elicit the opposite response-homeostatic depression via removal of excitatory receptors. There exist intriguing links between HSP and calcium channelopathies-such as forms of epilepsy, migraine, ataxia, and myasthenia. The episodic nature of some of these disorders suggests alternating periods of stable and unstable function. Uncovering information about how calcium channels are regulated in the context of HSP could be relevant toward understanding these and other disorders.
    Frontiers in Cellular Neuroscience 02/2014; 8:40. DOI:10.3389/fncel.2014.00040 · 4.29 Impact Factor
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    • "Modulation of Ca v 2.1 Gating by BHQ ''WT'' NMJs [F ratio at $1 s = 1.22 ± 0.09], EPSPs showed significantly less STF in ''S218L''-expressing NMJs (F ratio at $ 1 s = 0.99 ± 0.04; p = 0.01 by t test; Figures 9A and 9B). These results confirm that the synaptic defects that are associated with the S218L mutation (Kaja et al., 2010; van den Maagdenberg et al., 2010) are reproduced by the ''S218L'' at the Drosophila NMJ. BHQ (5 mM) essentially restored STF in ''S218L'' NMJs: there was no significant difference in STF of ''WT'' controls (F ratio at $1 s = 1.22 ± 0.09) and ''S218L'' with BHQ (F ratio at $1 s = 1.20 ± 0.10, p = 0.70; Figures 9A–9C). "
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    ABSTRACT: Voltage-gated ion channels exhibit complex properties, which can be targeted in pharmacological therapies for disease. Here, we report that the pro-oxidant, tert-butyl dihydroquinone (BHQ), modulates Cav2.1 Ca(2+) channels in ways that oppose defects in channel gating and synaptic transmission resulting from a familial hemiplegic migraine mutation (S218L). BHQ slows deactivation, inhibits voltage-dependent activation, and potentiates Ca(2+)-dependent facilitation of Cav2.1 channels in transfected HEK293T cells. These actions of BHQ help offset the gain of function and reduced Ca(2+)-dependent facilitation of Cav2.1 channels with the S218L mutation. Transgenic expression of the mutant channels at the Drosophila neuromuscular junction causes abnormally elevated evoked postsynaptic potentials and impaired synaptic plasticity, which are largely restored to the wild-type phenotypes by BHQ. Our results reveal a mechanism by which a Cav2.1 gating modifier can ameliorate defects associated with a disease-causing mutation in Cav2.1.
    Neuron 01/2014; 81(1):91-102. DOI:10.1016/j.neuron.2013.10.056 · 15.05 Impact Factor
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