Reelin signaling modulates GABA_B 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^cKO) 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^cKO organotypic slice cultures could be rescued by co-culture with wild-type organotypic slice cultures. Moreover, the GABA_B receptor (GABA_BR) agonist baclofen failed to activate and the antagonist CGP35348 failed to block GABA_BRs in Reln^cKO mice. Immunolabeling of Reln^cKO cortical slices revealed a reduction in GABA_BR1 and GABA_BR2 surface expression at the plasma membrane and western blot of Reln^cKO cortical tissue revealed decreased phosphorylation of the GABA_BR2 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_BR function. (Figure presented.). Cover Image for this issue: https://doi.org/10.1111/jnc.15054.