Endogenous Positive Allosteric Modulation of GABAA Receptors by Diazepam binding inhibitor

Summary Benzodiazepines (BZs) allosterically modulateγ- aminobutyric acidtype-A receptors (GABA A Rs) to increase inhibitory synaptic strength. Diazepam binding inhibitor(DBI) protein is a BZ site ligand expressed endogenouslyin the brain, but functional evidence for BZ-mimicking positive modulatory actions has been elusive. We demonstrate an endogenouspotentiation of GABAergicsynaptic 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 in which BZ binding to α3 subunit-containing GABA A Rs is disrupted. Viral transduction of DBI into nRT is sufficient to rescue the endogenouspotentiation of GABAergictransmission in nm1054 mice. Both mutations enhance thalamocortical spike-and- wavedischarges characteristic of absence epilepsy. Together, these results indicate that DBI mediates endogenousnucleus-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.