Wendy Klement1, Rita Garbelli2, Emma Zub1, Laura Rossini2, Laura Tassi3, Benoit Girard4, Marine Blaquiere1, Federica Bertaso4, Julie Perroy4, Frederic de Bock1, Nicola Marchi5. 1. Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Institute of Functional Genomics (UMR 5203 CNRS - U 1191 INSERM, University of Montpellier), Montpellier, France. 2. Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico C. Besta, Milano, Italy. 3. C. Munari Epilepsy Surgery Centre, Ospedale Niguarda, Milano, Italy. 4. Laboratory of Pathophysiology of Synaptic Transmission, Institute of Functional Genomics (UMR 5203 CNRS - U 1191 INSERM, University of Montpellier), Montpellier, France. 5. Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Institute of Functional Genomics (UMR 5203 CNRS - U 1191 INSERM, University of Montpellier), Montpellier, France. Electronic address: nicola.marchi@igf.cnrs.fr.
Abstract
BACKGROUND: Cerebrovascular dysfunction and inflammation occur in epilepsy. Here we asked whether pericytes, a pivotal cellular component of brain capillaries, undergo pathological modifications during experimental epileptogenesis and in human epilepsy. We evaluated whether pro-inflammatory cytokines, present in the brain during seizures, contribute to pericyte morphological modifications. METHODS: In vivo, unilateral intra-hippocampal kainic acid (KA) injections were performed in NG2DsRed/C57BL6 mice to induce status epilepticus (SE), epileptogenesis, and spontaneous recurrent seizures (SRS). NG2DsRed mice were used to visualize pericytes during seizure progression. The effect triggered by recombinant IL-1β, TNFα, or IL-6 on pericytes was evaluated in NG2DsRed hippocampal slices and in human-derived cell culture. Human brain specimens obtained from temporal lobe epilepsy (TLE) with or without sclerosis (HS) and focal cortical dysplasia (FCD-IIb) were evaluated for pericyte-microglial cerebrovascular assembly. RESULTS: A disarray of NG2DsRed+ pericyte soma and ramifications was found 72 h post-SE and 1 week post-SE (epileptogenesis) in the hippocampus. Pericyte modifications topographically overlapped with IBA1+ microglia clustering around the capillaries with cases of pericytes lodged within the microglial cells. Microglial clustering around the NG2DsRed pericytes lingered at SRS. Pericyte proliferation (Ki67+) occurred 72 h post-SE and during epileptogenesis and returned towards control levels at SRS. Human epileptic brain tissues showed pericyte-microglia assemblies with IBA1/HLA microglial cells outlining the capillary wall in TLE-HS and FCD-IIb specimens. Inflammatory mediators contributed to pericyte modifications, in particular IL-1β elicited pericyte morphological changes and pericyte-microglia clustering in NG2DsRed hippocampal slices. Modifications also occurred when pro-inflammatory cytokines were added to an in vitro culture of pericytes. CONCLUSIONS: These results indicate the occurrence of pericytosis during seizures and introduce a pericyte-microglial mediated mechanism of blood-brain barrier dysfunction in epilepsy.
BACKGROUND:Cerebrovascular dysfunction and inflammation occur in epilepsy. Here we asked whether pericytes, a pivotal cellular component of brain capillaries, undergo pathological modifications during experimental epileptogenesis and in humanepilepsy. We evaluated whether pro-inflammatory cytokines, present in the brain during seizures, contribute to pericyte morphological modifications. METHODS: In vivo, unilateral intra-hippocampal kainic acid (KA) injections were performed in NG2DsRed/C57BL6 mice to induce status epilepticus (SE), epileptogenesis, and spontaneous recurrent seizures (SRS). NG2DsRed mice were used to visualize pericytes during seizure progression. The effect triggered by recombinant IL-1β, TNFα, or IL-6 on pericytes was evaluated in NG2DsRed hippocampal slices and in human-derived cell culture. Human brain specimens obtained from temporal lobe epilepsy (TLE) with or without sclerosis (HS) and focal cortical dysplasia (FCD-IIb) were evaluated for pericyte-microglial cerebrovascular assembly. RESULTS: A disarray of NG2DsRed+ pericyte soma and ramifications was found 72 h post-SE and 1 week post-SE (epileptogenesis) in the hippocampus. Pericyte modifications topographically overlapped with IBA1+ microglia clustering around the capillaries with cases of pericytes lodged within the microglial cells. Microglial clustering around the NG2DsRed pericytes lingered at SRS. Pericyte proliferation (Ki67+) occurred 72 h post-SE and during epileptogenesis and returned towards control levels at SRS. Humanepileptic brain tissues showed pericyte-microglia assemblies with IBA1/HLA microglial cells outlining the capillary wall in TLE-HS and FCD-IIb specimens. Inflammatory mediators contributed to pericyte modifications, in particular IL-1β elicited pericyte morphological changes and pericyte-microglia clustering in NG2DsRed hippocampal slices. Modifications also occurred when pro-inflammatory cytokines were added to an in vitro culture of pericytes. CONCLUSIONS: These results indicate the occurrence of pericytosis during seizures and introduce a pericyte-microglial mediated mechanism of blood-brain barrier dysfunction in epilepsy.
Authors: Gabryella S P Santos; Luiz A V Magno; Marco A Romano-Silva; Akiva Mintz; Alexander Birbrair Journal: Neurosci Bull Date: 2018-10-26 Impact factor: 5.203
Authors: Leon C D Smyth; Justin Rustenhoven; Thomas I-H Park; Patrick Schweder; Deidre Jansson; Peter A Heppner; Simon J O'Carroll; Edward W Mee; Richard L M Faull; Maurice Curtis; Mike Dragunow Journal: J Neuroinflammation Date: 2018-05-11 Impact factor: 8.322
Authors: Alberto Sepulveda-Rodriguez; Pinggan Li; Tahiyana Khan; James D Ma; Colby A Carlone; P Lorenzo Bozzelli; Katherine E Conant; Patrick A Forcelli; Stefano Vicini Journal: eNeuro Date: 2019-04-23