Reelin signaling modulates GABAB receptor function in the neocortex

• Published in: Journal of neurochemistry Vol. 156; no. 5; pp. 589 - 603
• Main Authors: Hamad, Mohammad I. K., Jbara, Abdalrahim, Rabaya, Obada, Petrova, Petya, Daoud, Solieman, Melliti, Nesrine, Meseke, Maurice, Lutz, David, Petrasch‐Parwez, Elisabeth, Schwitalla, Jan Claudius, Mark, Melanie D., Herlitze, Stefan, Reiss, Gebhard, Herz, Joachim, Förster, Eckart
• Format: Journal Article
• Language: English
• Published: New York Blackwell Publishing Ltd 01.03.2021
• Subjects: ApoER2 and VLDLR; Apolipoprotein E; Baclofen; Blocking; calcium imaging; Cerebral cortex; Deactivation; GABAB receptors; Neocortex; network activity; Phosphorylation; Proteolysis; Receptors; Reelin; Reelin protein; Serine; γ-Aminobutyric acid B receptors
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14990

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 (RelncKO) 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 RelncKO organotypic slice cultures could be rescued by co‐culture with wild‐type organotypic slice cultures. Moreover, the GABAB receptor (GABABR) agonist baclofen failed to activate and the antagonist CGP35348 failed to block GABABRs in RelncKO mice. Immunolabeling of RelncKO cortical slices revealed a reduction in GABABR1 and GABABR2 surface expression at the plasma membrane and western blot of RelncKO cortical tissue revealed decreased phosphorylation of the GABABR2 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 GABABR function. Cover Image for this issue: https://doi.org/10.1111/jnc.15054. We suggested the following modification of synaptic function after conditional Reelin knockout in the cerebral cortex: After Reelin deficiency, the pre‐synaptic reelin signaling cascade via the Reelin receptors ApoER2 and Vldlr and the adaptor protein Dab1, is no longer activated. This causes a decreased phosphorylation of pre‐synaptic GABAB receptors at S892, while phosphorylation at S783 increases, likely induced by AMP‐activated protein kinase (AMPK). As a consequence, GABAB receptors are degraded, calcium influx via NMDA receptors and synaptic vesicle release is increased. We believe that our findings revealed a new synaptic function of reelin expressed by cortical interneurons during cortical development. Cover Image for this issue: https://doi.org/10.1111/jnc.15054.