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

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 2

Seizure-induced sustained arteriole constriction is associated with an initial transient rise in astrocytic endfoot Ca2+.

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Seizure-induced sustained arteriole constriction is associated with an i...
(A) Schematics of awake-mouse experimental setup. (B) Reconstruction in 3D of the superficial barrel cortex from a Slc1a3-Cre/ERT RCL-GCaMP3 mouse. Astrocytes expressing GCaMP3 are shown in green; the vasculature is loaded with Rhod B-dextran shown in red. (C) Cross section of a penetrating arteriole (p.a.) enwrapped by an endfoot (e.f.). Images show preictal (top), severe vasoconstriction and a large astrocyte Ca2+ rise triggered by MES during the ictal period (middle), and the postictal period (bottom). (D). Summary time course of arteriolar diameter in Slc1a3-Cre/ERT RCL-GCaMP3 mice (N = 5). To limit photobleaching and/or photodamage, measurements were taken for 60 seconds every 300 seconds. Arrow and vertical dotted line indicate MES (0.2 second). Inset: Temporal close-up of percent diameter changes during the ictal (t test, t[4] = 8.06, P < 0.001) and postictal (t test, t[4] = 4.04, P = 0.007) period, and representative trace of diameter response to 0.2-second MES. (E) Summary time course of endfoot Ca2+ measurements in the same experiment as diameter measures (N = 4). Vertical dotted line indicates MES (0.2 second). Inset: Temporal close-up of endfoot Ca2+ response during the ictal (t test, t[3] = 6.36, P = 0.007) and postictal (t test, t[3] = 1.63, P = 0.20) period and representative trace of endfoot Ca2+ to 0.2-second MES. (F) Summary time course of astrocyte arbor Ca2+ measurements in the same experiment as diameter measures (N = 4). Vertical dotted line indicates MES (0.2 second). Inset: Temporal close-up of astrocyte arbor Ca2+ response during the ictal (t test, t[3] = 3.43, P = 0.04) and postictal (t test, t[3] = 1.56, P = 0.2) period and representative trace of astrocyte arbor Ca2+ to 0.2-second MES. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.