REELIN SOURCES IN CORTICAL DEVELOPMENT AND NEURODEVELOPMENTAL DISORDERS

Reelin (Reln) is a large glycoprotein regulating multiple steps of mammalian cortical development and its blood and brain levels are sensitive to the environment. In humans, homozygous or compound RELN mutations are associated with neuronal migration disorders, while heterozygous mutations and decreased cortical Reln levels are associated with neurodevelopmental disorders (NDDs), including autism spectrum disorders, schizophrenia and bipolar disorders. Similarly, rodent homozygous reln mutants (Reeler) present profound alterations in cortical lamination, while heterozygous animals display normal lamination but alterations in neuronal cytoarchitecture and plasticity, related to cognitive and behavioral deficits. Importantly, during development, Reln is secreted by sequential cellular sources: Cajal-Retzius cells (CRs) represent the main source during embryonic stages and cortical GABAergic interneurons (INs) are the main source in adulthood. However, whether Reln sources play distinct roles in cortical cytoarchitecture, wiring and related behavior remains unknown. Here, using conditional genetic models specifically ablating reln in CRs and/or INs, we describe specific and cooperative roles for Reln sources in cortical lamination along cortical areas. Furthermore, reln elimination in either CRs or a subpopulation of INs, results in specific or opposite deficits in several behavioral tests relevant for NDDs, supporting specific functions for Reln sources in cortical wiring and adult behavior. We further investigate the molecular and cellular mechanisms underlying the modulation of Reln levels by the environment, focusing on serotonin (5-HT) signaling. These results will provide critical insights into the role of Reln deficits in cortical development and its implication across the phenotypic diversity of NDDs.