Dataset Information

Identification of a neurovascular signaling pathway regulating seizures in mice.

ABSTRACT:

Objective

A growing body of evidence suggests that increased blood-brain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures.

Methods

An experimental model of kainate-induced seizures was used in genetically modified mice, including mice deficient in tPA (tPA (-/-) ), its inhibitor neuroserpin (Nsp (-/-) ), or both (Nsp:tPA (-/-) ), and in mice conditionally deficient in the platelet-derived growth factor receptor alpha (PDGFR?).

Results

Compared to wild-type (WT) mice, Nsp (-/-) mice have significantly reduced latency to seizure onset and generalization; whereas tPA (-/-) mice have the opposite phenotype, as do Nsp:tPA (-/-) mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizure-resistant tPA (-/-) mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, tPA (-/-) , and Nsp (-/-) mice are also observed in electroencephalogram recordings in vivo, but absent in ex vivo electrophysiological recordings where regulation of the BBB is no longer necessary to maintain the extracellular environment. Finally, we demonstrate that these effects on seizure progression are mediated through signaling by PDGFR? on perivascular astrocytes.

Interpretation

Together, these data identify a specific molecular pathway involving tPA-mediated PDGFR? signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFR? signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.

SUBMITTER: Fredriksson L

PROVIDER: S-EPMC4531055 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Publications

Identification of a neurovascular signaling pathway regulating seizures in mice.

Fredriksson Linda L Stevenson Tamara K TK Su Enming J EJ Ragsdale Margaret M Moore Shannon S Craciun Stefan S Schielke Gerald P GP Murphy Geoffrey G GG Lawrence Daniel A DA

Annals of clinical and translational neurology 20150501 7

<h4>Objective</h4>A growing body of evidence suggests that increased blood-brain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures.<h4>Methods</h4>An experimental model of kainate-induced seizures was used in genetically modified mice, including mice deficient in tPA (tPA (-/-) ), its ...[more]

PMID: 26273685

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Dataset Information

Identification of a neurovascular signaling pathway regulating seizures in mice.

Objective

Methods

Results

Interpretation

Publications

Identification of a neurovascular signaling pathway regulating seizures in mice.

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