title: Impact of inhibitory constraint of interneurons on neuronal excitability.
abstract: Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ-subunit-containing GABAA receptors (GABAARs). In the present study we demonstrate the importance of GABAAR δ-subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ-subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice (Gabrd/Gad mice). Deficits in GABAAR δ-subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship toward decreased excitability compared with those from Cre(-/-) littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared with Cre(-/-) controls. These data demonstrate a critical role for GABAAR δ-subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.
authors.affiliation: Medical Scientist Training Program and Graduate Program in Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts; and.
authors.forename: Vallent
authors.initials: V
authors.lastname: Lee
authors.forename: Jamie
authors.initials: J
authors.lastname: Maguire
mesh_terms: D000200:Action Potentials; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials; D007395:Interneurons / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D055369:Miniature Postsynaptic Potentials; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism
chemical_list: C583130:Gabrd protein, mouse; D010446:Peptide Fragments; D011963:Receptors, GABA-A; D005968:Glutamate Decarboxylase; C505593:glutamic acid decarboxylase 65 (524-543), mouse
keywords: GABA; floxed Gabrd; interneurons; seizure susceptibility; tonic inhibition
references.citation: Nat Neurosci. 2003 May;6(5):484-90
references.pmid: 12679782
references.citation: J Neurosci. 2011 Dec 14;31(50):18198-210
references.pmid: 22171026
references.citation: J Neurosci. 2007 Aug 1;27(31):8219-25
references.pmid: 17670968
references.citation: J Neurophysiol. 2008 Jul;100(1):526-32
references.pmid: 18463187
references.citation: Neuron. 2012 Jan 12;73(1):23-34
references.pmid: 22243744
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3662-7
references.pmid: 14993607
references.citation: J Neurosci. 2002 May 15;22(10):RC223
references.pmid: 12006605
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19152-7
references.pmid: 17146052
references.citation: Nat Neurosci. 2010 Feb;13(2):205-12
references.pmid: 20023655
references.citation: Prog Brain Res. 2010;186:113-37
references.pmid: 21094889
references.citation: J Neurosci. 2004 Sep 29;24(39):8629-39
references.pmid: 15456836
references.citation: Epilepsy Res Suppl. 1992;7:301-13
references.pmid: 1334669
references.citation: Nat Neurosci. 2007 Jan;10(1):40-8
references.pmid: 17159992
references.citation: J Neurosci. 2010 Jan 6;30(1):110-5
references.pmid: 20053893
references.citation: J Neurosci. 2008 Feb 6;28(6):1421-6
references.pmid: 18256262
references.citation: J Neurosci. 2009 Jul 29;29(30):9592-601
references.pmid: 19641122
references.citation: Proc Biol Sci. 1998 Jan 7;265(1390):63-9
references.pmid: 9470216
references.citation: Brain Res Dev Brain Res. 2001 Dec 14;132(1):1-13
references.pmid: 11744102
references.citation: Prog Brain Res. 2007;163:235-43
references.pmid: 17765722
references.citation: PLoS One. 2012;7(9):e46044
references.pmid: 23029379
references.citation: J Physiol. 2007 Aug 1;582(Pt 3):1163-78
references.pmid: 17525114
references.citation: J Pharmacol Exp Ther. 2004 Sep;310(3):1234-45
references.pmid: 15126642
references.citation: Epilepsia. 2002;43 Suppl 5:3-8
references.pmid: 12121286
references.citation: J Neurosci. 2009 Dec 2;29(48):15341-50
references.pmid: 19955387
references.citation: J Neurophysiol. 2013 Apr;109(7):1746-63
references.pmid: 23324316
references.citation: Brain Res. 1997 Aug 1;764(1-2):237-43
references.pmid: 9295216
references.citation: Nat Commun. 2011 Jul 05;2:376
references.pmid: 21730957
references.citation: J Physiol. 2010 Jun 1;588(Pt 11):1861-9
references.pmid: 20308251
references.citation: Trends Neurosci. 2007 Jul;30(7):343-9
references.pmid: 17532059
references.citation: J Neurophysiol. 2006 May;95(5):2796-807
references.pmid: 16452257
references.citation: Prog Brain Res. 2007;160:59-87
references.pmid: 17499109
references.citation: J Neurophysiol. 2008 Aug;100(2):932-44
references.pmid: 18509076
references.citation: Nature. 2001 Jan 4;409(6816):88-92
references.pmid: 11343119
references.citation: Neuron. 2003 May 8;38(3):433-45
references.pmid: 12741990
references.citation: Hum Mol Genet. 2004 Jul 1;13(13):1315-9
references.pmid: 15115768
references.citation: Nat Neurosci. 2005 Jun;8(6):797-804
references.pmid: 15895085
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14439-44
references.pmid: 14623958
references.citation: J Neurosci. 2007 Feb 28;27(9):2155-62
references.pmid: 17329412
references.citation: Brain Res. 2001 Nov 23;919(2):242-9
references.pmid: 11701136
references.citation: Nat Rev Neurosci. 2005 Mar;6(3):215-29
references.pmid: 15738957