title: Tubacin prevents neuronal migration defects and epileptic activity caused by rat Srpx2 silencing in utero.
abstract: Altered development of the human cerebral cortex can cause severe malformations with often intractable focal epileptic seizures and may participate in common pathologies, notably epilepsy. This raises important conceptual and therapeutic issues. Two missense mutations in the sushi repeat-containing protein SRPX2 had been previously identified in epileptic disorders with or without structural developmental alteration of the speech cortex. In the present study, we aimed to decipher the precise developmental role of SRPX2, to have a better knowledge on the consequences of its mutations, and to start addressing therapeutic issues through the design of an appropriate animal model. Using an in utero Srpx2 silencing approach, we show that SRPX2 influences neuronal migration in the developing rat cerebral cortex. Wild-type, but not the mutant human SRPX2 proteins, rescued the neuronal migration phenotype caused by Srpx2 silencing in utero, and increased alpha-tubulin acetylation. Following in utero Srpx2 silencing, spontaneous epileptiform activity was recorded post-natally. The neuronal migration defects and the post-natal epileptic consequences were prevented early in embryos by maternal administration of tubulin deacetylase inhibitor tubacin. Hence epileptiform manifestations of developmental origin could be prevented in utero, using a transient and drug-based therapeutic protocol.
authors.affiliation: INSERM UMR_S901, Parc Scientifique de Luminy, 13273 Marseille, France.
authors.forename: Manal
authors.initials: M
authors.lastname: Salmi
authors.forename: Nadine
authors.initials: N
authors.lastname: Bruneau
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cillario
authors.forename: Natalia
authors.initials: N
authors.lastname: Lozovaya
authors.forename: Annick
authors.initials: A
authors.lastname: Massacrier
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Buhler
authors.forename: Robin
authors.initials: R
authors.lastname: Cloarec
authors.forename: Timur
authors.initials: T
authors.lastname: Tsintsadze
authors.forename: Françoise
authors.initials: F
authors.lastname: Watrin
authors.forename: Vera
authors.initials: V
authors.lastname: Tsintsadze
authors.forename: Céline
authors.initials: C
authors.lastname: Zimmer
authors.forename: Claude
authors.initials: C
authors.lastname: Villard
authors.forename: Daniel
authors.initials: D
authors.lastname: Lafitte
authors.forename: Carlos
authors.initials: C
authors.lastname: Cardoso
authors.forename: Lan
authors.initials: L
authors.lastname: Bao
authors.forename: Gaetan
authors.initials: G
authors.lastname: Lesca
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rudolf
authors.forename: Françoise
authors.initials: F
authors.lastname: Muscatelli
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pauly
authors.forename: Ilgam
authors.initials: I
authors.lastname: Khalilov
authors.forename: Pascale
authors.initials: P
authors.lastname: Durbec
authors.forename: Yehezkel
authors.initials: Y
authors.lastname: Ben-Ari
authors.forename: Nail
authors.initials: N
authors.lastname: Burnashev
authors.forename: Alfonso
authors.initials: A
authors.lastname: Represa
authors.forename: Pierre
authors.initials: P
authors.lastname: Szepetowski
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D000813:Anilides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; C099179:Srpx protein, rat; D014404:Tubulin; C474316:tubacin
keywords: Srpx2; developmental epilepsy; in utero prevention; neuronal migration; tubulin acetylation