title: Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction.
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.
authors.affiliation: Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Itai
authors.initials: I
authors.lastname: Weissberg
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720-3140, USA.
authors.forename: Lydia
authors.initials: L
authors.lastname: Wood
authors.affiliation: Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Lyn
authors.initials: L
authors.lastname: Kamintsky
authors.affiliation: Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720-3140, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Vazquez
authors.affiliation: Departments of Physiology and Cell Biology, Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Dan Z
authors.initials: DZ
authors.lastname: Milikovsky
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
authors.forename: Allyson
authors.initials: A
authors.lastname: Alexander
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720-3140, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Oppenheim
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720-3140, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ardizzone
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn 53105, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Becker
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Frigerio
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
authors.forename: Marion S
authors.initials: MS
authors.lastname: Buckwalter
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Huguenard
authors.affiliation: 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.
authors.forename: Alon
authors.initials: A
authors.lastname: Friedman
authors.affiliation: 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.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaufer
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced; D012709:Serum Albumin / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D012709:Serum Albumin; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: ALK5; Albumin; Astrocytes; Blood–brain barrier (BBB); Epilepsy; Post-insult epilepsy (PIE); Post-traumatic epilepsy (PTE); Seizures; Synaptogenesis; TGF-β
references.citation: J Vis Exp. 2010;(45). pii: 2270. doi: 10.3791/2270
references.pmid: 21113117
references.citation: Nat Rev Neurol. 2011 Jan;7(1):31-40
references.pmid: 21135885
references.citation: Brain. 2005 Aug;128(Pt 8):1931-42
references.pmid: 15888537
references.citation: J Neurosci. 2006 May 3;26(18):4891-900
references.pmid: 16672663
references.citation: Brain Behav Immun. 2011 Oct;25(7):1281-9
references.pmid: 21473909
references.citation: Epilepsia. 2012 Mar;53(3):539-48
references.pmid: 22372630
references.citation: Nature. 2012 Jun 21;486(7403):410-4
references.pmid: 22722203
references.citation: J Cereb Blood Flow Metab. 2012 Jul;32(7):1139-51
references.pmid: 22252235
references.citation: Curr Opin Neurobiol. 2012 Jun;22(3):438-45
references.pmid: 22036016
references.citation: J Neurosci. 2012 Sep 19;32(38):13100-10
references.pmid: 22993427
references.citation: Neurobiol Dis. 2012 Dec;48(3):495-506
references.pmid: 22782081
references.citation: Epilepsia. 2012 Nov;53 Suppl 6:1-6
references.pmid: 23134489
references.citation: Epilepsia. 2012 Nov;53 Suppl 6:31-6
references.pmid: 23134493
references.citation: Epilepsia. 2012 Nov;53(11):1898-906
references.pmid: 22967085
references.citation: Epilepsia. 2012 Nov;53(11):1887-97
references.pmid: 22984896
references.citation: J Biol Chem. 2012 Nov 30;287(49):41432-45
references.pmid: 23055518
references.citation: Seizure. 2013 Mar;22(2):144-50
references.pmid: 23182422
references.citation: Trends Neurosci. 2013 Mar;36(3):174-84
references.pmid: 23298414
references.citation: J Mol Neurosci. 2013 May;50(1):109-23
references.pmid: 22936246
references.citation: Nat Rev Neurosci. 2013 May;14(5):311-21
references.pmid: 23595014
references.citation: Neurobiol Dis. 2014 Mar;63:74-84
references.pmid: 24321435
references.citation: Trends Neurosci. 2014 Feb;37(2):55-65
references.pmid: 24355813
references.citation: Neuromolecular Med. 2014 Jun;16(2):457-72
references.pmid: 24519742
references.citation: Glia. 2014 Aug;62(8):1227-40
references.pmid: 24733756
references.citation: Ann Neurol. 2014 Jun;75(6):864-75
references.pmid: 24659129
references.citation: Epilepsia. 2000;41 Suppl 6:S144-52
references.pmid: 10999536
references.citation: Cell Mol Neurobiol. 2001 Dec;21(6):675-91
references.pmid: 12043841
references.citation: Stroke. 2003 Jan;34(1):177-86
references.pmid: 12511771
references.citation: Nat Rev Neurosci. 2003 Feb;4(2):113-20
references.pmid: 12563282
references.citation: J Neurosci. 2003 Sep 24;23(25):8692-700
references.pmid: 14507968
references.citation: J Neurosci. 2004 Sep 8;24(36):7829-36
references.pmid: 15356194
references.citation: Exp Neurol. 1983 Feb;79(2):422-33
references.pmid: 6822273
references.citation: Epilepsia. 1984 Apr;25(2):259-68
references.pmid: 6705755
references.citation: Neuroscience. 1991;42(2):351-63
references.pmid: 1716744
references.citation: Life Sci. 1992;51(7):467-77
references.pmid: 1640796
references.citation: Neurosci Lett. 1995 Jan 16;184(1):52-4
references.pmid: 7739806
references.citation: Eur J Neurosci. 1995 Apr 1;7(4):630-46
references.pmid: 7620614
references.citation: Nat Med. 1996 Dec;2(12):1382-5
references.pmid: 8946841
references.citation: Exp Brain Res. 1997 Mar;114(1):1-10
references.pmid: 9125446
references.citation: Cell. 2005 Feb 11;120(3):421-33
references.pmid: 15707899
references.citation: J Neurosci. 2005 Apr 6;25(14):3638-50
references.pmid: 15814795
references.citation: Brain. 2007 Feb;130(Pt 2):535-47
references.pmid: 17121744
references.citation: Brain. 2007 Feb;130(Pt 2):521-34
references.pmid: 17124188
references.citation: Neurobiol Dis. 2007 Feb;25(2):367-77
references.pmid: 17188501
references.citation: Epilepsia. 2007 Apr;48(4):732-42
references.pmid: 17319915
references.citation: Neuroscience. 2008 Jan 2;151(1):272-92
references.pmid: 18093740
references.citation: J Neurosci. 2008 Feb 27;28(9):2119-30
references.pmid: 18305246
references.citation: J Neurol Neurosurg Psychiatry. 2008 Jul;79(7):774-7
references.pmid: 17991703
references.citation: J Neurotrauma. 2008 Jul;25(7):769-83
references.pmid: 18627255
references.citation: J Cereb Blood Flow Metab. 2008 Oct;28(10):1722-32
references.pmid: 18594557
references.citation: J Neurosci. 2008 Sep 24;28(39):9599-609
references.pmid: 18815246
references.citation: Brain. 2008 Dec;131(Pt 12):3256-65
references.pmid: 18952671
references.citation: Neurobiol Dis. 2009 Apr;34(1):121-32
references.pmid: 19320047
references.citation: J Neurosci. 2009 Jul 15;29(28):8927-35
references.pmid: 19605630
references.citation: Epilepsy Res. 2009 Aug;85(2-3):142-9
references.pmid: 19362806
references.citation: J Neurosci. 2009 Aug 26;29(34):10588-99
references.pmid: 19710312
references.citation: Cell. 2009 Oct 16;139(2):380-92
references.pmid: 19818485
references.citation: Neuroscience. 2010 Mar 10;166(1):312-32
references.pmid: 20004712
references.citation: Nat Med. 2010 Apr;16(4):413-9
references.pmid: 20348922
references.citation: Nat Rev Neurol. 2010 Jul;6(7):393-403
references.pmid: 20551947
references.citation: Brain. 2011 Mar;134(Pt 3):732-46
references.pmid: 21278085
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):E440-9
references.pmid: 21788491
references.citation: Glia. 2014 Dec;62(12):1917-31
references.pmid: 25042347
references.citation: Neuroscientist. 2015 Feb;21(1):62-83
references.pmid: 24609207
references.citation: J Neurotrauma. 2005 Jul;22(7):719-32
references.pmid: 16004576
references.citation: Nature. 2010 Nov 11;468(7321):223-31
references.pmid: 21068831