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