Journal
JOURNAL OF NEUROCHEMISTRY
Volume 156, Issue 5, Pages 589-603Publisher
WILEY
DOI: 10.1111/jnc.14990
Keywords
ApoER2 and VLDLR; calcium imaging; GABAB receptors; network activity; Reelin
Categories
Funding
- National Institutes of Health [R37 HL63762, R01 NS093382, R01 NS108115, RF1 AG053391]
- Consortium for Frontotemporal Dementia Research
- Bright Focus Foundation
- FoRUM of the Ruhr-Universitat Bochum
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Reelin plays a crucial role in controlling early network activity by modulating GABA(B)R function, affecting the excitability of the cortical network.
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(B)R) agonist baclofen failed to activate and the antagonist CGP35348 failed to block GABA(B)Rs in Reln(cKO)mice. Immunolabeling of Reln(cKO)cortical slices revealed a reduction in GABA(B)R1 and GABA(B)R2 surface expression at the plasma membrane and western blot of Reln(cKO)cortical tissue revealed decreased phosphorylation of the GABA(B)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(B)R function.
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