Identification of a neurovascular signaling pathway regulating seizures in mice.
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 (PDGFRα).


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 PDGFRα on perivascular astrocytes.


CONCLUSIONS
Together, these data identify a specific molecular pathway involving tPA-mediated PDGFRα signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFRα signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.
Division of Vascular Biology, Department of Medical Biochemistry & Biophysics, Karolinska Institutet Stockholm, Sweden ; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School Ann Arbor, Michigan.
Linda
L
Fredriksson
Department of Molecular and Integrative Physiology, University of Michigan Medical School Ann Arbor, Michigan.
Tamara K
TK
Stevenson
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School Ann Arbor, Michigan.
Enming J
EJ
Su
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School Ann Arbor, Michigan.
Margaret
M
Ragsdale
Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School Ann Arbor, Michigan.
Shannon
S
Moore
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School Ann Arbor, Michigan.
Stefan
S
Craciun
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School Ann Arbor, Michigan.
Gerald P
GP
Schielke
Department of Molecular and Integrative Physiology, University of Michigan Medical School Ann Arbor, Michigan ; Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School Ann Arbor, Michigan.
Geoffrey G
GG
Murphy
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School Ann Arbor, Michigan ; Department of Molecular and Integrative Physiology, University of Michigan Medical School Ann Arbor, Michigan.
Daniel A
DA
Lawrence