Activity‐dependent calcium, oxygen, and vascular responses in a mouse model of familial hemiplegic migraine type 1

Khennouf, Lila; Gesslein, Bodil; Lind, Barbara Lykke; Maagdenberg, Arn M. J. M. van den; Lauritzen, Martin

doi:10.1002/ana.24707

Cited by 25 publications

(38 citation statements)

References 44 publications

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“…Differences in function between several types of neurons in healthy networks in the cortex [60] could be the reason for distinct effects of FHM1 mutations on various neuronal networks leading to dynamic perturbations in the excitatory/inhibitory balance in the brain. It has been reported recently that tissue anoxia could be the underlying mechanism for strong aura in FHM1 patients [61]. In this study, Ca 2+ signals have been reduced during normal network activity in a FHM1 mouse model compared to WT mice, it has been proposed that this event could explain deficits in neurovascular responses in the FHM1 KI mice, leading to a brain weakness in patients with FHM1 mutations [61].…”

Section: Neuronal Network-dependent Synaptic Plasticity In Fhm1 Mutanmentioning

confidence: 50%

Mouse Models of Familial Hemiplegic Migraine for Studying Migraine Pathophysiology

Dehghani

Karataş

2019

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Migraine, an extremely disabling neurological disorder, has a strong genetic component. Since monogenic migraines (resulting from mutations or changes in a single gene) may help researchers discover migraine pathophysiology, transgenic mice models harboring gene mutations identified in Familial Hemiplegic Migraine (FHM) patients have been generated. Studies in these FHM mutant mice models have shed light on the mechanisms of migraine and may aid in the identification of novel targets for treatment. More specifically, the studies shed light on how gene mutations, hormones, and other factors impact the pathophysiology of migraine. The models may also be of relevance to researchers outside the field of migraine as some of their aspects are relevant to pain in general. Additionally, because of the comorbidities associated with migraine, they share similarities with the mutant mouse models of epilepsy, stroke, and perhaps depression. Here, we review the experimental data obtained from these mutant mice and focus on how they can be used to investigate the pathophysiology of migraine, including synaptic plasticity, neuroinflammation, metabolite alterations, and molecular and behavioral mechanisms of pain.

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Section: Neuronal Network-dependent Synaptic Plasticity In Fhm1 Mutanmentioning

confidence: 50%

Mouse Models of Familial Hemiplegic Migraine for Studying Migraine Pathophysiology

Dehghani

Karataş

2019

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“…CSD is a slow depolarizing wave that is involved in migraine, traumatic brain injury, and stroke 43 . CSD evokes an initial vasoconstriction (phase I), immediately followed by a transient hyperemic response (phase II), which is superseded by a longlasting vasoconstriction of arterioles and capillaries (phase III) that impairs the NVC 7,44 . During CSD, the sphincter exhibited pronounced diameter changes ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, our technique for making craniotomies was validated previously by measuring cerebral blood flow while drilling the craniotomy, ensuring that no spreading depolarization was triggered during surgical preparation. Using this technique, we could show that no spreading depolarization was elicited 44 . Moreover, prior to our first spreading depolarization, we measured whisker responses, and mice that did not exhibit normal vessel diameter dilation, i.e., less than 5% dilation, to whisker stimulation were discarded from the dataset, ensuring that no spreading depolarization were triggered before recordings started.…”

Section: Methodsmentioning

confidence: 97%

Precapillary sphincters maintain perfusion in the cerebral cortex

et al. 2020

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Active nerve cells release vasodilators that increase their energy supply by dilating local blood vessels, a mechanism termed neurovascular coupling and the basis of BOLD functional neuroimaging signals. Here, we reveal a mechanism for cerebral blood flow control, a precapillary sphincter at the transition between the penetrating arteriole and first order capillary, linking blood flow in capillaries to the arteriolar inflow. The sphincters are encircled by contractile mural cells, which are capable of bidirectional control of the length and width of the enclosed vessel segment. The hemodynamic consequence is that precapillary sphincters can generate the largest changes in the cerebrovascular flow resistance of all brain vessel segments, thereby controlling capillary flow while protecting the downstream capillary bed and brain tissue from adverse pressure fluctuations. Cortical spreading depolarization constricts sphincters and causes vascular trapping of blood cells. Thus, precapillary sphincters are bottlenecks for brain capillary blood flow.

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“…It is noted that Ca 2+ concentration in astrocytes during CSD is higher than that of wt mice in FHM1 model mice, Cacna1a R192Q/R192Q [57]. Although CACNA1A is predominantly localized in neurons [58], Cacna1a R192Q/R192Q shows the increased activity of astrocytes as observed in Atp1a2 +/− mice.…”

Section: Discussionmentioning

confidence: 99%

Astrocytes in Atp1a2‐deficient heterozygous mice exhibit hyperactivity after induction of cortical spreading depression

et al. 2020

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The ATP1A2 coding α2 subunit of Na,K‐ATPase, which is predominantly located in astrocytes, is a causative gene of familial hemiplegic migraine type 2 (FHM2). FHM2 model mice (Atp1a2tmCKwk/+) are susceptible to cortical spreading depression (CSD), which is profoundly related to migraine aura and headache. However, astrocytic properties during CSD have not been examined in FHM2 model mice. Using Atp1a2tmCKwk/+ crossed with transgenic mice expressing G‐CaMP7 in cortical neurons and astrocytes (Atp1a2+/−), we analyzed the changes in Ca2+ concentrations during CSD. The propagation speed of Ca2+ waves and the percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/− were higher than those in wild‐type mice. Increased percentages of astrocytes with elevated Ca2+ concentrations in Atp1a2+/− may contribute to FHM2 pathophysiology.

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Activity‐dependent calcium, oxygen, and vascular responses in a mouse model of familial hemiplegic migraine type 1

Cited by 25 publications

References 44 publications

Mouse Models of Familial Hemiplegic Migraine for Studying Migraine Pathophysiology

Mouse Models of Familial Hemiplegic Migraine for Studying Migraine Pathophysiology

Precapillary sphincters maintain perfusion in the cerebral cortex

Astrocytes in Atp1a2‐deficient heterozygous mice exhibit hyperactivity after induction of cortical spreading depression

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