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Neurobiol Dis. 2015 Jun;78:115-25. doi: 10.1016/j.nbd.2015.02.029. Epub 2015 Mar 30.

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

Author information

1
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
2
Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720-3140, USA.
3
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720-3140, USA.
4
Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
5
Department of Neuropathology, University of Bonn Medical Center, Bonn 53105, Germany.
6
Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
7
Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. Electronic address: alonf@bgu.ac.il.
8
Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720-3140, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720-3140, USA; Canadian Institute for Advanced Research (CIFAR) Program in Child and Brain Development Toronto, ON M5G 1Z8, Canada. Electronic address: danielak@berkeley.edu.

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.

KEYWORDS:

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

PMID:
25836421
PMCID:
PMC4426044
DOI:
10.1016/j.nbd.2015.02.029
[Indexed for MEDLINE]
Free PMC Article

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