Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction

Itai Weissberg, Lydia Wood, Lyn Kamintsky, Oscar Vazquez, Dan Z. Milikovsky, Allyson Alexander, Hannah Oppenheim, Carolyn Ardizzone, Albert Becker, Federica Frigerio, Annamaria Vezzani, Marion S. Buckwalter, John R. Huguenard, Alon Friedman, Daniela Kaufer

Research output: Contribution to journalArticlepeer-review

Abstract

Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE.

Original languageEnglish
Pages (from-to)115-125
Number of pages11
JournalNeurobiology of Disease
Volume78
DOIs
Publication statusPublished - Jun 1 2015

Keywords

  • Albumin
  • ALK5
  • Astrocytes
  • Blood-brain barrier (BBB)
  • Epilepsy
  • Post-insult epilepsy (PIE)
  • Post-traumatic epilepsy (PTE)
  • Seizures
  • Synaptogenesis
  • TGF-β

ASJC Scopus subject areas

  • Neurology

Fingerprint Dive into the research topics of 'Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction'. Together they form a unique fingerprint.

Cite this