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Seizures elevate gliovascular unit Ca2+ and cause sustained vasoconstriction
Cam Ha T. Tran, Antis G. George, G. Campbell Teskey, Grant R. Gordon
Cam Ha T. Tran, Antis G. George, G. Campbell Teskey, Grant R. Gordon
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Research Article Neuroscience

Seizures elevate gliovascular unit Ca2+ and cause sustained vasoconstriction

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Abstract

Seizures can result in a severe hypoperfusion/hypoxic attack that causes postictal memory and behavioral impairments. However, neither postictal changes to microvasculature nor Ca2+ changes in key cell types controlling blood perfusion have been visualized in vivo, leaving essential components of the underlying cellular mechanisms unclear. Here, we use 2-photon microvascular and Ca2+ imaging in awake mice to show that seizures result in a robust vasoconstriction of cortical penetrating arterioles, which temporally mirrors the prolonged postictal hypoxia. The vascular effect was dependent on cyclooxygenase 2, as pretreatment with ibuprofen prevented postictal vasoconstriction. Moreover, seizures caused a rapid elevation in astrocyte endfoot Ca2+ that was confined to the seizure period, and vascular smooth muscle cells displayed a significant increase in Ca2+ both during and following seizures, lasting up to 75 minutes. Our data show enduring postictal vasoconstriction and temporal activities of 2 cell types within the neurovascular unit that are associated with seizure-induced hypoperfusion/hypoxia. These findings support prevention of this event may be a novel and tractable treatment strategy in patients with epilepsy who experience extended postseizure impairments.

Authors

Cam Ha T. Tran, Antis G. George, G. Campbell Teskey, Grant R. Gordon

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Figure 5

Seizure-induced sustained arteriole constriction is associated with rapid and prolonged vascular smooth muscle cell Ca2+ elevation.

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Seizure-induced sustained arteriole constriction is associated with rapi...
(A) Schematics of awake-mouse experimental setup. (B) Reconstruction in 3D of the superficial barrel cortex from a PdgfrB-Cre RCL-GCaMP6s mouse. VSMC expressing GCaMP6s are shown in green; the vasculature loaded with Rhod B-dextran is shown in red. (C) Summary time course of arteriole diameter responses (N = 5). Arrow and vertical dotted line indicate MES (0.2 second). To limit photobleaching and/or photodamage, measurements were taken for 60 seconds every 300 seconds. Inset: Temporal close-up of percent diameter changes during the ictal (t test, t[4] = 3.74, P = 0.02) and postictal (t test, t[4] = 3.58, P = 0.023) period and representative trace of diameter in response to 0.2-second MES. (D) Summary time course of VSMC Ca2+ elevations in the same experiments as diameter measures. Inset: Temporal close-up of percentage VSMC Ca2+ changes during the ictal (t test, t[4] = 2.42, P = 0.036) and postictal (t test, t[4] = 3.03, P = 0.038) period. Inset: representative trace of VSMC Ca2+ in response to 0.2-second MES. (E) Cross section of a penetrating arteriole (red) with VSMC expressing GCaMP6s (green). Images show baseline (top), the ictal period (middle), and the postictal period (bottom). (F) Left: Summary of calculated Spearman’s r values between changes in arteriole diameter and VSMC Ca2+ during the postictal period. Right: Correlation between VSMC Ca2+ and arteriole diameter during baseline (100 seconds before MES) and postictal period (4500 seconds). Each data point represents a 10-second bin and averages across all 5 animals. Data represent mean ± SEM. *P < 0.05, **P < 0.01.

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