PMID- 23380687
OWN - NLM
STAT- MEDLINE
DCOM- 20130923
LR  - 20211021
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Print)
IS  - 0014-2999 (Linking)
VI  - 703
IP  - 1-3
DP  - 2013 Mar 5
TI  - Enhancing the function of alpha5-subunit-containing GABAA receptors promotes 
      action potential firing of neocortical neurons during up-states.
PG  - 18-24
LID - S0014-2999(13)00049-6 [pii]
LID - 10.1016/j.ejphar.2013.01.034 [doi]
AB  - Neocortical neurons mediate the sedative and anticonvulsant properties of 
      benzodiazepines. These agents enhance synaptic inhibition via positive modulation 
      of gamma-aminobutyric acid (GABAA) receptors harboring alpha1-, alpha2-, alpha3- or alpha5-protein 
      subunits. Benzodiazepine-sensitive GABAA receptors containing the alpha5-subunit are 
      abundant in the neocortex, but their impact in controlling neuronal firing 
      patterns is unknown. Here we studied how the discharge rates of cortical neurons 
      are modified by a positive (SH-053-2'F-R-CH3) and a negative (L 655,708) 
      alpha5-subunit-preferring allosteric modulator in comparison to diazepam, the 
      classical non-selective benzodiazepine. Drug actions were characterized in slice 
      cultures from wild-type and alpha5(H105R) knock-in mice by performing extracellular 
      multi-unit-recordings. In knock-in mice, receptors containing the alpha5 subunit are 
      insensitive to benzodiazepines. The non-selective positive allosteric modulator 
      diazepam decreased the discharge rates of neocortical neurons during episodes of 
      ongoing neuronal activity (up states). In contrast to diazepam, the alpha5-preferring 
      positive modulator SH-053-2'F-R-CH3 accelerated action potential firing during up 
      states. This promoting action was absent in slices from alpha5(H105R) mice, 
      confirming that it is mediated by the alpha5-subunit. Consistent with these 
      observations, the negative alpha5-selective modulator L 655,708 inhibited up state 
      action potential activity in slices from wild-type mice. The opposing actions of 
      diazepam and SH-053-2'F-R-CH3, which both enhance GABAA receptor function but 
      differ in subtype-selectivity, uncovers contrasting roles of GABAA receptor 
      subtypes in controlling the firing rates of cortical neurons. These findings may 
      have important implications for the design of novel anaesthetic and 
      anticonvulsant benzodiazepines displaying an improved efficacy and fewer side 
      effects.
CI  - Copyright (c) 2013 Elsevier B.V. All rights reserved.
FAU - Drexler, Berthold
AU  - Drexler B
AD  - Experimental Anaesthesiology Section, Department of Anaesthesiology and Intensive 
      Care Medicine, Eberhard-Karls-University, 72072 Tuebingen, Germany. 
      berthold.drexler@uni-tuebingen.de
FAU - Zinser, Stefan
AU  - Zinser S
FAU - Huang, Shengming
AU  - Huang S
FAU - Poe, Michael M
AU  - Poe MM
FAU - Rudolph, Uwe
AU  - Rudolph U
FAU - Cook, James M
AU  - Cook JM
FAU - Antkowiak, Bernd
AU  - Antkowiak B
LA  - eng
GR  - R01 NS076517/NS/NINDS NIH HHS/United States
GR  - R01 MH096463/MH/NIMH NIH HHS/United States
GR  - R01 MH046851/MH/NIMH NIH HHS/United States
GR  - R01GM086448/GM/NIGMS NIH HHS/United States
GR  - R01 GM086448/GM/NIGMS NIH HHS/United States
GR  - MH046851/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130201
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (GABA-A Receptor Agonists)
RN  - 0 (Imidazoles)
RN  - 0 (L 655,708)
RN  - 0 (Receptors, GABA-A)
RN  - 0 (SH-053-2'F-R-CH3)
RN  - Q3JTX2Q7TU (Diazepam)
SB  - IM
MH  - Action Potentials/drug effects
MH  - Animals
MH  - Diazepam/*analogs & derivatives/pharmacology
MH  - Female
MH  - GABA-A Receptor Agonists/*pharmacology
MH  - Imidazoles/*pharmacology
MH  - In Vitro Techniques
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Neocortex/cytology
MH  - Neurons/*drug effects/physiology
MH  - Receptors, GABA-A/*physiology
PMC - PMC3996676
MID - NIHMS471851
COIS- Statement of conflicts of Interest: None.
EDAT- 2013/02/06 06:00
MHDA- 2013/09/24 06:00
PMCR- 2014/04/23
CRDT- 2013/02/06 06:00
PHST- 2012/09/10 00:00 [received]
PHST- 2013/01/12 00:00 [revised]
PHST- 2013/01/16 00:00 [accepted]
PHST- 2013/02/06 06:00 [entrez]
PHST- 2013/02/06 06:00 [pubmed]
PHST- 2013/09/24 06:00 [medline]
PHST- 2014/04/23 00:00 [pmc-release]
AID - S0014-2999(13)00049-6 [pii]
AID - 10.1016/j.ejphar.2013.01.034 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2013 Mar 5;703(1-3):18-24. doi: 10.1016/j.ejphar.2013.01.034. 
      Epub 2013 Feb 1.