@article{e7b8e3e28bc6488b87a147c80b04bbaa,
title = "Endogenous Positive Allosteric Modulation of GABAA Receptors by Diazepam binding inhibitor",
abstract = "Benzodiazepines (BZs) allosterically modulate γ-aminobutyric acid type-A receptors (GABAARs) to increase inhibitory synaptic strength. Diazepam binding inhibitor (DBI) protein is a BZ site ligand expressed endogenously in the brain, but functional evidence for BZ-mimicking positive modulatory actions has been elusive. We demonstrate an endogenous potentiation of GABAergic synaptic transmission and responses to GABA uncaging in the thalamic reticular nucleus (nRT) that is absent in both nm1054 mice, in which the Dbi gene is deleted, and mice inwhich BZ binding to α3 subunit-containing GABAARs is disrupted. Viral transduction of DBI into nRT is sufficient to rescue the endogenous potentiation of GABAergic transmission in nm1054 mice. Both mutations enhance thalamocortical spike-and-wave discharges characteristic of absence epilepsy. Together, these results indicate that DBI mediates endogenous nucleus-specific BZ-mimicking ({"}endozepine{"}) roles to modulate nRT function and suppress thalamocortical oscillations. Enhanced DBI signaling might serve as a therapy for epilepsy and other neurological disorders",
author = "Christian, {Catherine A.} and Herbert, {Anne G.} and Holt, {Rebecca L.} and Kathy Peng and Sherwood, {Kyla D.} and Susanne Pangratz-Fuehrer and Uwe Rudolph and Huguenard, {John R.}",
note = "Funding Information: We thank Isabel Parada for expert assistance with histology experiments, Lance Lee and Mark Fleming for providing nm1054 founder mice, Richard Reimer for providing the DBI-T2A-GFP plasmid and helpful discussions, Craig Garner and Michael Lochrie for helpful discussions regarding virus generation, and Istvan Mody and Stefano Vicini for useful critiques of the manuscript. This work was supported by NIH grants NS034774 (J.R.H.), NS006477 (J.R.H.), T32 NS007280 (C.A.C.), an Epilepsy Foundation Research Fellowship (C.A.C.), and a Katharine McCormick Advanced Postdoctoral Fellowship from Stanford School of Medicine (C.A.C.). C.A.C. and J.R.H. designed the studies, analyzed EEG data, and wrote the manuscript; C.A.C. performed and analyzed the in vitro electrophysiology and virus experiments and prepared the figures; C.A.C., A.G.H., R.L.H., K.P, and K.D.S. performed the EEG experiments; S.P.-F. performed pilot studies; U.R. provided α3(H126R) founder mice and edited the manuscript. ",
year = "2013",
month = jun,
day = "19",
doi = "10.1016/j.neuron.2013.04.026",
language = "English (US)",
volume = "78",
pages = "1063--1074",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "6",
}