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Glial Calcium Waves are Triggered by Seizure Activity and Not Essential for Initiating Ictal Onset or Neurovascular Coupling.

ABSTRACT: It has been postulated that glia play a critical role in modifying neuronal activity, mediating neurovascular coupling, and in seizure initiation. We investigated the role of glia in ictogenesis and neurovascular coupling through wide-field multicell and 2-photon single cell imaging of calcium and intrinsic signal imaging of cerebral blood volume in an in vivo rat model of focal neocortical seizures. Ictal events triggered a slowly propagating glial calcium wave that was markedly delayed after both neuronal and hemodynamic onset. Glial calcium waves exhibited a stereotypical spread that terminated prior to seizure offset and propagated to an area ~60% greater than the propagation area of neural and vascular signals. Complete blockage of glial activity with fluoroacetate resulted in no change in either neuronal or hemodynamic activity. These ictal glial waves were blocked by carbenoxolone, a gap junction blocker. Our in vivo data reveal that ictal events trigger a slowly propagating, stereotypical glial calcium wave, mediated by gap junctions, that is spatially and temporally independent of neuronal and hemodynamic activities. We introduce a novel ictally triggered propagating glial calcium wave calling into question the criticality of glial calcium wave in both ictal onset and neurovascular coupling.

SUBMITTER: Baird-Daniel E

PROVIDER: S-EPMC6433182 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Glial Calcium Waves are Triggered by Seizure Activity and Not Essential for Initiating Ictal Onset or Neurovascular Coupling.

Baird-Daniel Eliza E Daniel Andy G S AGS Wenzel Michael M Li Dan D Liou Jyun-You JY Laffont Philippe P Zhao Mingrui M Yuste Rafael R Ma Hongtao H Schwartz Theodore H TH

Cerebral cortex (New York, N.Y. : 1991) 20170601 6

It has been postulated that glia play a critical role in modifying neuronal activity, mediating neurovascular coupling, and in seizure initiation. We investigated the role of glia in ictogenesis and neurovascular coupling through wide-field multicell and 2-photon single cell imaging of calcium and intrinsic signal imaging of cerebral blood volume in an in vivo rat model of focal neocortical seizures. Ictal events triggered a slowly propagating glial calcium wave that was markedly delayed after b ...[more]

PMID: 28369176

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Project description:Background and purposeControlling vascular tone involves K(+) efflux through endothelial cell small- and intermediate-conductance calcium-activated potassium channels (K(Ca)2.3 and K(Ca)3.1, respectively). We investigated the expression of these channels in astrocytes and the possibility that, by a similar mechanism, they might contribute to neurovascular coupling.Experimental approachTransgenic mice expressing enhanced green fluorescent protein (eGFP) in astrocytes were used to assess K(Ca)2.3 and K(Ca)3.1 expression by immunohistochemistry and RT-PCR. K(Ca) currents in eGFP-positive astrocytes were determined in situ using whole-cell patch clamp electrophysiology. The contribution of K(Ca)3.1 to neurovascular coupling was investigated in pharmacological experiments using electrical field stimulation (EFS) to evoke parenchymal arteriole dilatation in FVB/NJ mouse brain slices and whisker stimulation to evoke changes in cerebral blood flow in vivo, measured by laser Doppler flowmetry.Key resultsK(Ca)3.1 immunoreactivity was restricted to astrocyte processes and endfeet and RT-PCR confirmed astrocytic K(Ca)2.3 and K(Ca)3.1 mRNA expression. With 200 nM [Ca(2+)](i) , the K(Ca)2.1-2.3/K(Ca)3.1 opener NS309 increased whole-cell currents. CyPPA, a K(Ca)2.2/K(Ca)2.3 opener, was without effect. With 1 µM [Ca(2+)](i) , the K(Ca)3.1 inhibitor TRAM-34 reduced currents whereas apamin (K(Ca)2.1-2.3 blocker) had no effect. CyPPA also inhibited currents evoked by NS309 in HEK293 cells expressing K(Ca)3.1. EFS-evoked Fluo-4 fluorescence confirmed astrocyte endfoot recruitment into neurovascular coupling. TRAM-34 inhibited EFS-evoked arteriolar dilatation by 50% whereas charybdotoxin, a blocker of K(Ca)3.1 and the large-conductance K(Ca) channel, K(Ca)1.1, inhibited dilatation by 82%. TRAM-34 reduced the cortical hyperaemic response to whisker stimulation by 40%.Conclusion and implicationsAstrocytes express functional K(Ca)3.1 channels, and these contribute to neurovascular coupling.

Project description:Importance:Literature on ictal magnetoencephalography (MEG) in clinical practice and the relationship to other modalities is limited because of the brevity of routine studies. Objective:To investigate the utility and reliability of ictal MEG in the localization of the epileptogenic zone. Design, Setting, and Participants:A retrospective medical record review and prospective analysis of a novel ictal rhythm analysis method was conducted at a tertiary epilepsy center with a wide base of referrals for epilepsy surgery evaluation and included consecutive cases of patients who experienced epileptic seizures during routine MEG studies from March 2008 to February 2012. A total of 377 studies screened. Data were analyzed from November 2011 to October 2015. Main Outcomes and Measures:Presurgical workup and interictal and ictal MEG data were reviewed. The localizing value of using extended-source localization of a narrow band identified visually at onset was analyzed. Results:Of the 44 included patients, the mean (SD) age at the time of recording was 19.3 (14.9) years, and 25 (57%) were male. The mean duration of recording was 51.2 minutes. Seizures were provoked by known triggers in 3 patients and were spontaneous otherwise. Twenty-five patients (57%) had 1 seizure, 6 (14%) had 2, and 13 (30%) had 3 or more. Magnetoencephalography single equivalent current dipole analysis was possible in 29 patients (66%), of whom 8 (28%) had no clear interictal discharges. Sublobar concordance between ictal and interictal dipoles was seen in 18 of 21 patients (86%). Three patients (7%) showed clear ictal MEG patterns without electroencephalography changes. Ictal MEG dipoles correlated with the lobe of onset in 7 of 8 patients (88%) who underwent intracranial electroencephalography evaluations. Reasons for failure to identify ictal dipoles included diffuse or poor dipolar ictal patterns, no MEG changes, and movement artifact. Resection of areas containing a minimum-norm estimate of a narrow band at onset, not single equivalent current dipole, was associated with sustained seizure freedom. Conclusions and Significance:Ictal MEG data can provide reliable localization, including in cases that are difficult to localize by other modalities. These findings support the use of extended-source localization for seizures recorded during MEG.

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Glial Calcium Waves are Triggered by Seizure Activity and Not Essential for Initiating Ictal Onset or Neurovascular Coupling.

Publications

Glial Calcium Waves are Triggered by Seizure Activity and Not Essential for Initiating Ictal Onset or Neurovascular Coupling.

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