TY - JOUR
T1 - Subregion-Specific Impacts of Genetic Loss of Diazepam Binding Inhibitor on Synaptic Inhibition in the Murine Hippocampus
AU - Courtney, Connor D.
AU - Christian, Catherine A.
N1 - Funding Information:
We thank Dr. Susanne Mandrup for the gift of founder mice for our DBI knockout colony and Amin Ghane, Steven Rhoads, and Ammar Ujjainwala for assistance with mouse colony maintenance and genotyping. This work was supported by the Brain and Behavior Research Foundation (NARSAD Young Investigator Grant 24086, C.A.C.) and start-up funds from the University of Illinois at Urbana-Champaign (C.A.C.). C.A.C is also supported by National Institute of Neurological Disorders and Stroke R01 NS105825. C.A.C. designed the experiments; C.D.C. performed experiments, analyzed data, and prepared the figures; C.D.C. and C.A.C. wrote the manuscript.
Funding Information:
We thank Dr. Susanne Mandrup for the gift of founder mice for our DBI knockout colony and Amin Ghane, Steven Rhoads, and Ammar Ujjainwala for assistance with mouse colony maintenance and genotyping. This work was supported by the Brain and Behavior Research Foundation (NARSAD Young Investigator Grant 24086 , C.A.C.) and start-up funds from the University of Illinois at Urbana-Champaign (C.A.C.). C.A.C is also supported by National Institute of Neurological Disorders and Stroke R01 NS105825 . C.A.C. designed the experiments; C.D.C. performed experiments, analyzed data, and prepared the figures; C.D.C. and C.A.C. wrote the manuscript.
Publisher Copyright:
© 2018 IBRO
PY - 2018/9/15
Y1 - 2018/9/15
N2 - Benzodiazepines 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 (GABA A Rs) 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 GABA A Rs 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 GABA A R-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.
AB - Benzodiazepines 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 (GABA A Rs) 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 GABA A Rs 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 GABA A R-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.
KW - GABA
KW - benzodiazepine
KW - diazepam
KW - electrophysiology
KW - flumazenil
KW - paired-pulse ratio
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UR - http://www.scopus.com/inward/citedby.url?scp=85050754871&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2018.07.012
DO - 10.1016/j.neuroscience.2018.07.012
M3 - Article
C2 - 30031126
AN - SCOPUS:85050754871
SN - 0306-4522
VL - 388
SP - 128
EP - 138
JO - Neuroscience
JF - Neuroscience
ER -