Seizure-induced microvascular injury is associated with impaired neurovascular coupling and blood–brain barrier dysfunction

Ofer Prager, Lyna Kamintsky, Luisa A. Hasam-Henderson, Karl Schoknecht, Vera Wuntke, Ismini Papageorgiou, Jutta Swolinsky, Valeria Muoio, Guy Bar-Klein, Udi Vazana, Uwe Heinemann, Alon Friedman, Richard Kovács

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Objective: Blood–brain barrier (BBB) impairment, redistribution of pericytes, and disturbances in cerebral blood flow may contribute to the increased seizure propensity and neurological comorbidities associated with epilepsy. However, despite the growing evidence of postictal disturbances in microcirculation, it is not known how recurrent seizures influence pericytic membrane currents and subsequent vasodilation. Methods: Here, we investigated successive changes in capillary neurovascular coupling and BBB integrity during recurrent seizures induced by 4-aminopyridine or low-Mg2+ conditions. To avoid the influence of arteriolar dilation and cerebral blood flow changes on the capillary response, we measured seizure-associated pericytic membrane currents, capillary motility, and permeability changes in a brain slice preparation. Arteriolar responses to 4-aminopyridine–induced seizures were further studied in anesthetized Sprague Dawley rats by using electrocorticography and tissue oxygen recordings simultaneously with intravital imaging of arteriolar diameter, BBB permeability, and cellular damage. Results: Within the preserved vascular network in hippocampal slice cultures, pericytes regulated capillary diameter in response to vasoactive agents and neuronal activity. Seizures induced distinct patterns of membrane currents that contributed to the regulation of pericytic length. During the course of recurrent seizures, individual vasodilation responses eroded and BBB permeability increased, despite unaltered neurometabolic coupling. Reduced vascular responsiveness was associated with mitochondrial depolarization in pericytes. Subsequent capillary constriction preceded BBB opening, suggesting that pericyte injury mediates the breach in capillary integrity. In vivo findings were consistent with slice experiments, showing seizure-related neurovascular decoupling and BBB dysfunction in small cortical arterioles, accompanied by perivascular cellular injury despite normoxic conditions. Significance: Our study presents a direct observation of gradually developing neurovascular decoupling during recurrent seizures and suggests pericytic injury as an inducer of vascular dysfunction in epilepsy.

Original languageEnglish
Pages (from-to)322-336
Number of pages15
Issue number2
StatePublished - 1 Feb 2019


  • blood–brain barrier
  • neurovascular coupling
  • pericytes
  • slice culture
  • vascular dysfunction

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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