Endogenous Positive Allosteric Modulation of GABAA Receptors by Diazepam binding inhibitor

Catherine A. Christian, Anne G. Herbert, Rebecca L. Holt, Kathy Peng, Kyla D. Sherwood, Susanne Pangratz-Fuehrer, Uwe Rudolph, John R. Huguenard

Research output: Contribution to journalArticlepeer-review

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

Original languageEnglish (US)
Pages (from-to)1063-1074
Number of pages12
JournalNeuron
Volume78
Issue number6
DOIs
StatePublished - Jun 19 2013
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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