Enhanced circadian phase resetting in R192Q Ca<sub>v</sub>2.1 calcium channel migraine mice

Oosterhout, Floor van; Michel, Stephan; Deboer, Tom; Houben, Thijs; Ven, R.C.G. van de; Albus, Henk; Westerhout, Joost; Vansteensel, Mariska J.; Ferrari, Michel D.; Maagdenberg, Arn M. J. M. van den; Meijer, Johanna H.

doi:10.1002/ana.21418

Cited by 33 publications

(28 citation statements)

References 56 publications

(84 reference statements)

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“…This is a rather unexpected finding since in knock-out models Ca V 2.1 has never been described to be involved in the maintenance of circadian rhythmicity per se , although a knock-in model in which a human familial hemiplegic migraine mutation was introduced showed an enhanced circadian phase setting phenotype [29].…”

Section: Resultsmentioning

confidence: 95%

Ablation of CaV2.1 Voltage-Gated Ca2+ Channels in Mouse Forebrain Generates Multiple Cognitive Impairments

et al. 2013

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Voltage-gated CaV2.1 (P/Q-type) Ca2+ channels located at the presynaptic membrane are known to control a multitude of Ca2+-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is restricted by the limited adequacy of existing transgenic CaV2.1 mouse models. Global CaV2.1 knock-out mice lacking the α1 subunit Cacna1a gene product exhibit early postnatal lethality which makes them unsuitable to analyse the relevance of CaV2.1 Ca2+ channels for complex behaviour in adult mice. Consequently we established a forebrain specific CaV2.1 knock-out model by crossing mice with a floxed Cacna1a gene with mice expressing Cre-recombinase under the control of the NEX promoter. This novel mouse model enabled us to investigate the contribution of CaV2.1 to complex cognitive functions, particularly learning and memory. Electrophysiological analysis allowed us to test the specificity of our conditional knock-out model and revealed an impaired synaptic transmission at hippocampal glutamatergic synapses. At the behavioural level, the forebrain-specific CaV2.1 knock-out resulted in deficits in spatial learning and reference memory, reduced recognition memory, increased exploratory behaviour and a strong attenuation of circadian rhythmicity. In summary, we present a novel conditional CaV2.1 knock-out model that is most suitable for analysing the in vivo functions of CaV2.1 in the adult murine forebrain.

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Section: Resultsmentioning

confidence: 95%

Ablation of CaV2.1 Voltage-Gated Ca2+ Channels in Mouse Forebrain Generates Multiple Cognitive Impairments

et al. 2013

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“…The high level of expression of Cav2.1, β 4 , and α 2 δ-2 in IT retinas is intriguing. Although retinal pathway involvement in the adaptation mechanism to circadian phase-shift has been excluded previously in Cav2.1-mutated migraine mice 65 this hypothesis was never directly tested. The mammalian retina contains a clock that generates molecular circadian rhythms independent of the suprachiasmatic nucleus master clock, 66 but a calcium channel contribution was so far only reported for Cav1.2 67 , 68 …”

Section: Discussionmentioning

confidence: 99%

Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2

et al. 2013

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Mutations in the CACNA1F gene encoding the Cav1.4 Ca2+ channel are associated with X-linked congenital stationary night blindness type 2 (CSNB2). Despite the increasing knowledge about the functional behavior of mutated channels in heterologous systems, the pathophysiological mechanisms that result in vision impairment remain to be elucidated. This work provides a thorough functional characterization of the novel IT mouse line that harbors the gain-of-function mutation I745T reported in a New Zealand CSNB2 family.1 Electroretinographic recordings in IT mice permitted a direct comparison with human data. Our data supported the hypothesis that a hyperpolarizing shift in the voltage-dependence of channel activation—as seen in the IT gain-of-function mutant2—may reduce the dynamic range of photoreceptor activity. Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter. The organization of the outer plexiform layer was disrupted, and synaptic structures of photoreceptors had a variable, partly immature, appearance. The associated visual deficiency was substantiated in behavioral paradigms. The IT mouse line serves as a specific model for the functional phenotype of human CSNB2 patients with gain-of-function mutations and may help to further understand the dysfunction in CSNB.

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“…It is differentially expressed between LG/J and SM/J in both liver and white-fat and contains many SNPs in non-coding flanking and intronic regions having high-regulatory potential. This gene is associated with chronodisruption, the desynchronization of circadian rhythms [72], and with migraine headaches [73]. Recent research demonstrates an association among chronodisruption, migraine, and MetS components [74]–[76].…”

Section: Discussionmentioning

confidence: 99%

Genetic Effects at Pleiotropic Loci Are Context-Dependent with Consequences for the Maintenance of Genetic Variation in Populations

et al. 2011

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Context-dependent genetic effects, including genotype-by-environment and genotype-by-sex interactions, are a potential mechanism by which genetic variation of complex traits is maintained in populations. Pleiotropic genetic effects are also thought to play an important role in evolution, reflecting functional and developmental relationships among traits. We examine context-dependent genetic effects at pleiotropic loci associated with normal variation in multiple metabolic syndrome (MetS) components (obesity, dyslipidemia, and diabetes-related traits). MetS prevalence is increasing in Western societies and, while environmental in origin, presents substantial variation in individual response. We identify 23 pleiotropic MetS quantitative trait loci (QTL) in an F16 advanced intercross between the LG/J and SM/J inbred mouse strains (Wustl:LG,SM-G16; n = 1002). Half of each family was fed a high-fat diet and half fed a low-fat diet; and additive, dominance, and parent-of-origin imprinting genotypic effects were examined in animals partitioned into sex, diet, and sex-by-diet cohorts. We examine the context-dependency of the underlying additive, dominance, and imprinting genetic effects of the traits associated with these pleiotropic QTL. Further, we examine sequence polymorphisms (SNPs) between LG/J and SM/J as well as differential expression of positional candidate genes in these regions. We show that genetic associations are different in different sex, diet, and sex-by-diet settings. We also show that over- or underdominance and ecological cross-over interactions for single phenotypes may not be common, however multidimensional synthetic phenotypes at loci with pleiotropic effects can produce situations that favor the maintenance of genetic variation in populations. Our findings have important implications for evolution and the notion of personalized medicine.

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Enhanced circadian phase resetting in R192Q Ca_v2.1 calcium channel migraine mice

Cited by 33 publications

References 56 publications

Ablation of CaV2.1 Voltage-Gated Ca2+ Channels in Mouse Forebrain Generates Multiple Cognitive Impairments

Ablation of CaV2.1 Voltage-Gated Ca2+ Channels in Mouse Forebrain Generates Multiple Cognitive Impairments

Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2

Genetic Effects at Pleiotropic Loci Are Context-Dependent with Consequences for the Maintenance of Genetic Variation in Populations

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Enhanced circadian phase resetting in R192Q Cav2.1 calcium channel migraine mice

Cited by 33 publications

References 56 publications

Ablation of CaV2.1 Voltage-Gated Ca2+ Channels in Mouse Forebrain Generates Multiple Cognitive Impairments

Ablation of CaV2.1 Voltage-Gated Ca2+ Channels in Mouse Forebrain Generates Multiple Cognitive Impairments

Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2

Genetic Effects at Pleiotropic Loci Are Context-Dependent with Consequences for the Maintenance of Genetic Variation in Populations

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Enhanced circadian phase resetting in R192Q Ca_v2.1 calcium channel migraine mice