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.

Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

“…It is most likely inherited from the deceased asymptomatic maternal grandfather since it was also detected in the mother and in three maternal aunts yet absent from the maternal grandmother. Despite recent functional evidences regarding the role of SRPX2 in brain development,58 59 its definitive implication in cognitive disorders has already been questioned following the presence of the initially proposed mutations in EVS14 and in control individuals,60 and subsequently to the identification of a missense mutation in GRIN2A co-segregating with the epileptic status in the initial SRPX2 family 61. In another family, we identified a nonsense variant in SHROOM4 in a male proband yet also in his unaffected brothers, a finding that further challenges the implication of SHROOM4 in X-linked cognitive disorders (see online supplementary table S5, figure 2).…”

Genetics and mechanisms leading to human cortical malformations

“…It was demonstrated that Srpx2 influences acetylation of alphatubulin in vitro, where the expression of Srpx2 induced an increase in the acetylation activity and the silencing had the opposite effect. Moreover, the migration deficit was improved by prenatal administration of tubacin, a specific inhibitor of tubulin deacetylase HDAC6, and prevented the epileptiform activity caused by Srpx2 silencing in utero [279].…”

“…SRPX2 is expressed at various embryonic stages from the proliferative VZ/SVZ to the CP. Srpx2 downregulation lead to altered position of projection neurons in the developing rat cerebral cortex [279]. It was demonstrated that Srpx2 influences acetylation of alphatubulin in vitro, where the expression of Srpx2 induced an increase in the acetylation activity and the silencing had the opposite effect.…”

A novel 47.2Mb duplication on chromosomal bands Xq21.1–25 associated with mental retardation

“…Mutations in the SRPX2 gene have been identified as being responsible for rolandic seizures associated with oral and speech dyspraxia and mental retardation in a 3-generation French family (Roll et al, 2006). By in situ hybridization, Western blotting and immunohistochemical analyses, Salmi et al (2013) found that Srpx2 mRNA and protein were expressed in the embryonic rat brain during various developmental stages. Sia et al (2013) showed that SRPX2 reduction impaired development of ultrasonic vocalization in mice and suggested that SRPX2 is a synaptogenic factor that plays a role in the pathogenesis of language disorders.…”