Presentation
Specific roles and vulnerabilities of Reelin sources in neurodevelopmental disorders
Specific roles and vulnerabilities of Reelin sources in neurodevelopmental disorders
Reelin (Reln) is a large secreted glycoprotein with critical functions during cortical development, from neuronal migration, dendritic arborescence to synaptic plasticity and inflammation. Alterations of cortical Reln levels or Reln variants have been reported in human patients from the whole spectrum of neurodevelopmental disorders (NDDs), including neuronal migration disorders, autism spectrum disorders (ASD), schizophrenia (SCZ), bipolar disorders and major depressive disorders, with specific localization and degrees of alterations. Moreover, in rodent models, cortical Reln levels are highly sensitive to environmental challenge throughout life and similar alterations are detected in human with circulating Reln. Therefore, Reln stands has a highly potent hub for genetic and environment interactions in cortical development and the aetiology of NDDs. During development Reln is sequentially secreted by specific sources: first the Cajal-Retzius cells (CRs) at early embryogenesis and the sub-populations of interneurons (INs), which remain the main cortical source after the apoptosis of CRs during the first postnatal weeks. Since CRs and INs display sequential implications, with specific locations and Reln levels, my main hypothesis is that Reln sources display specific functions and specific vulnerabilities to environmental challenge, hereby contributing to the phenotypic diversity of NDDs. My small team includes a PhD Student (Judith Beaux) and a ingeneer (Lisa Vigier) and we concentrate on 3 main questions:
What are the specific functions of Reln sources in cortical development?
We have developed genetic models for conditional ablation of Reln in CRs and/or INs. We have yet unpublished results indicating that Reln sources achieve specific functions in cortical laminationa and in adult behaviors related to NDDs such as locomotion, prepulse inhibition and fear conditioning. We also observe that compensation mechanisms occur in the remaining source and that the co-ablation of both Reln sources reveal synergistic functions. We are now investigating the molecular actors of this compensation by scRNA sequencing and determining the specific roles of Reln sources on the wiring of monoaminergic fibers, the postnatal maturation of excitatory/inhibitory balance and synaptic functions.
How does environment control Reln levels?
We initially focus on the role of serotonin on the regulation of Reln levels since transient exposure to serotonin specific reuptake inhibitors (SSRI) alter Reln levels in both human serum and rodent brains, with opposite consequences at developmental versus adult stages. We show that only CRs and not INs display alterations of Reln levels upon postnatal exposure to SSRI (P2-P8), supporting specific vulnerabilities of Reln sources to environmental challenge. Moreover, the CR-specific Reln increase is much less pronounced upon embryonic exposure (E12-E18) supporting that modulation of Reln level by SSRIs occur during critical windows of vulnerabilities. We are now investigating the molecular mechanisms underneath at the transcriptomic, epigenetic and proteomic levels, and will expand our analysis to alternative environmental model of NDDs such as maternal inflammation (PolyI:C) and maternal separation.
How Reln is involved in NDDs phenotypic diversity?
Because Reln levels are altered in most NDDs but with specific localization and degrees, we expect that specific Reln sources area altered across development, although the story is highly complexified by the compensatory mechanisms observed. Nevertheless, we will try rescuing genetic and environmental models by transient postnatal supplementation in Reln, either globally by intra-veinous injection, or cell-specifically using transcranial neonatal injection with cre/lox systems. A critical attention will be paid to circulating levels at various developmental ages, to identify the potential role of Reln as a biomarker. In parallel, to confirm the translational role of Reln in NDDs, each Reln sources’ density will be quantified in brain tissues from patients with ASD or SCZ, and their matching controls.