Identification of a neurovascular signaling pathway regulating seizures in mice. Issue 7 (1st May 2015)

• Record Type: Journal Article
• Authors: Fredriksson, Linda; Stevenson, Tamara K.; Su, Enming J.; Ragsdale, Margaret; Moore, Shannon; Craciun, Stefan; Schielke, Gerald P.; Murphy, Geoffrey G.; Lawrence, Daniel A.
• Is Part Of: Annals of clinical and translational neurology. Volume 2:Issue 7(2015:Jul.)
• Page Start: 722
• Page End: 738
• Publication Date: 2015-05-01
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.209
• Languages: English
• ISSNs: 2328-9503

Abstract

<abstract abstract-type="main" id="acn3209-abs-0001"> <title>Abstract</title> <sec id="acn3209-sec-0001" sec-type="section"> <title>Objective</title> <p>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.</p> </sec> <sec id="acn3209-sec-0002" sec-type="section"> <title>Methods</title> <p>An experimental model of kainate‐induced seizures was used in genetically modified mice, including mice deficient in tPA (<italic>tPA</italic><sup><italic>−/−</italic></sup>), its inhibitor neuroserpin (<italic>Nsp</italic><sup><italic>−/−</italic></sup>), or both (<italic>Nsp:tPA</italic><sup><italic>−/−</italic></sup>), and in mice conditionally deficient in the platelet‐derived growth factor receptor alpha (PDGFR<italic>α</italic>).</p> </sec> <sec id="acn3209-sec-0003" sec-type="section"> <title>Results</title> <p>Compared to wild‐type (WT) mice, <italic>Nsp</italic><sup><italic>−/−</italic></sup> mice have significantly reduced latency to seizure onset and generalization; whereas <italic>tPA</italic><sup><italic>−/−</italic></sup> mice have the opposite phenotype, as do <italic>Nsp</italic>:<italic>tPA</italic><sup>−/−</sup> mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizure‐resistant <italic>tPA</italic><sup><italic>−/−</italic></sup> mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, <italic>tPA</italic><sup><italic>−/−</italic></sup>, and <italic>Nsp</italic><sup><italic>−/−</italic></sup> mice are also observed in electroencephalogram recordings <italic>in vivo</italic>, but absent in <italic>ex vivo</italic> 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<italic>α</italic> on perivascular astrocytes.</p> </sec> <sec id="acn3209-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Together, these data identify a specific molecular pathway involving tPA‐mediated PDGFR<italic>α</italic> signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFR<italic>α</italic> signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.</p> </sec> </abstract>