• Connor D Courtney and Catherine A Christian.
• Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
• Neuroscience. 2018 Sep 15; 388: 128-138.

AbstractBenzodiazepines are commonly prescribed to treat neurological conditions including epilepsy, insomnia, and anxiety. The discovery of benzodiazepine-specific binding sites on γ-aminobutyric acid type-A receptors (GABAARs) led to the hypothesis that the brain may produce endogenous benzodiazepine-binding site ligands. An endogenous peptide, diazepam binding inhibitor (DBI), which can bind these sites, is thought to be capable of both enhancing and attenuating GABAergic transmission in different brain regions. However, the role that DBI plays in modulating GABAARs in the hippocampus remains unclear. Here, we investigated the role of DBI in modulating synaptic inhibition in the hippocampus using a constitutive DBI knockout mouse. Miniature and evoked inhibitory postsynaptic currents (mIPSCs, eIPSCs) were recorded from CA1 pyramidal cells and dentate gyrus (DG) granule cells. Loss of DBI signaling increased mIPSC frequency and amplitude in CA1 pyramidal cells from DBI knockout mice compared to wild-types. In DG granule cells, conversely, the loss of DBI decreased mIPSC amplitude and increased mIPSC decay time, indicating bidirectional modulation of GABAAR-mediated transmission in specific subregions of the hippocampus. eIPSC paired-pulse ratios were consistent across genotypes, suggesting that alterations in mIPSC frequency were not due to changes in presynaptic release probability. Furthermore, cells from DBI knockout mice did not display altered responsiveness to pharmacological applications of diazepam, a benzodiazepine, nor flumazenil, a benzodiazepine-binding site antagonist. These results provide evidence that genetic loss of DBI alters synaptic inhibition in the adult hippocampus, and that the direction of DBI-mediated modulation can vary discretely between specific subregions of the same brain structure.Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

35 keywords...

hide…