Reelin Signaling Modulates GABA Receptor Function in the Neocortex

Reelin is a protein that is best known for its role in controlling neuronal layer formation in the developing cortex. Here, we studied its role for post-natal cortical network function, which is poorly explored. To preclude early cortical migration defects caused by Reelin deficiency, we used a conditional Reelin knock-out (Reln ) mouse, and induced Reelin deficiency post-natally. Induced Reelin deficiency caused hyperexcitability of the neocortical network in vitro and ex vivo. Blocking Reelin binding to its receptors ApoER2 and VLDLR resulted in a similar effect. Hyperexcitability in Reln organotypic slice cultures could be rescued by co-culture with wild-type organotypic slice cultures. Moreover, the GABA receptor (GABA R) agonist baclofen failed to activate and the antagonist CGP35348 failed to block GABA Rs in Reln mice. Immunolabeling of Reln cortical slices revealed a reduction in GABA R1 and GABA R2 surface expression at the plasma membrane and western blot of Reln cortical tissue revealed decreased phosphorylation of the GABA R2 subunit at serine 892 and increased phosphorylation at serine 783, reflecting receptor deactivation and proteolysis. These data show a role of Reelin in controlling early network activity, by modulating GABA R function. Cover Image for this issue: https://doi.org/10.1111/jnc.15054.