title: Disrupting the clustering of GABAA receptor α2 subunits in the frontal cortex leads to reduced γ-power and cognitive deficits.
abstract: In schizophrenia, cognitive dysfunction is highly predictive of poor patient outcomes and is not responsive to current medications. Postmortem studies have suggested that cognitive deficits in schizophrenia are correlated with modifications in the number and size of inhibitory synapses. To test if these modifications lead to cognitive deficits, we have created a dominant-negative virus [adeno-associated (AAV)-DN1] that disrupts the clustering of γ-aminobutyric acid type A receptors (GABA(A)Rs) at postsynaptic inhibitory specializations. When injected into the frontal cortex of mice, AAV-DN1 impairs GABA(A)R α2 subunit and GABA transporter 1 (GAT-1) clustering, but increases GABA(A)R α1 subunit clustering on the perisomatic region, with no influence on axon-initial segment clustering. Mice expressing AAV-DN1 have prepulse inhibition deficits and impairments in working memory. Significantly, these behavioral deficits are paralleled by a reduction in electroencephalography γ-power. Collectively, our study provides functional evidence revealing that GABAergic synapses in the prefrontal cortex directly contribute to cognition and γ-power.
authors.affiliation: Department of Neuroscience, Tufts University, Boston, MA 02111.
authors.forename: Rochelle M
authors.initials: RM
authors.lastname: Hines
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Hines
authors.forename: Catriona M
authors.initials: CM
authors.lastname: Houston
authors.forename: Jayanta
authors.initials: J
authors.lastname: Mukherjee
authors.forename: Philip G
authors.initials: PG
authors.lastname: Haydon
authors.forename: Verena
authors.initials: V
authors.lastname: Tretter
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004569:Electroencephalography; D005625:Frontal Lobe / Q000378:metabolism*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D005818:Genetic Engineering / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D011963:Receptors, GABA-A / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; C493920:Gabra2 protein, mouse; D011963:Receptors, GABA-A; C493414:Slc6a1 protein, mouse
references.citation: J Neurosci. 2013 Apr 24;33(17):7264-73
references.pmid: 23616535
references.citation: J Neurosci. 2008 Feb 6;28(6):1356-65
references.pmid: 18256255
references.citation: Biol Psychiatry. 2011 Mar 1;69(5):442-9
references.pmid: 21145041
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19878-83
references.pmid: 17170134
references.citation: Biol Psychiatry. 2006 Mar 15;59(6):536-45
references.pmid: 16139819
references.citation: Am J Psychiatry. 2001 Feb;158(2):256-65
references.pmid: 11156808
references.citation: Biol Psychiatry. 2012 Jan 15;71(2):114-9
references.pmid: 22036037
references.citation: Nature. 2009 Jun 4;459(7247):663-7
references.pmid: 19396156
references.citation: Annu Rev Neurosci. 2004;27:247-78
references.pmid: 15217333
references.citation: Nat Neurosci. 2010 Oct;13(10):1161-9
references.pmid: 20877280
references.citation: Am J Psychiatry. 1999 Nov;156(11):1709-19
references.pmid: 10553733
references.citation: Cereb Cortex. 2003 Dec;13(12):1369-74
references.pmid: 14615302
references.citation: J Biol Chem. 2010 Sep 17;285(38):29623-31
references.pmid: 20622020
references.citation: Nat Genet. 2005 Nov;37(11):1155
references.pmid: 16254554
references.citation: J Neurosci. 2008 Jun 11;28(24):6055-67
references.pmid: 18550748
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17998-8003
references.pmid: 19822762
references.citation: Neurosci Biobehav Rev. 2004 Nov;28(7):699-709
references.pmid: 15555679
references.citation: Nat Neurosci. 2010 Jan;13(1):76-83
references.pmid: 19915563
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12736-41
references.pmid: 15310851
references.citation: J Neurophysiol. 2004 Sep;92(3):1718-27
references.pmid: 15102896
references.citation: Mol Psychiatry. 2008 Feb;13(2):147-61
references.pmid: 17471287
references.citation: J Physiol. 1995 Dec 1;489 ( Pt 2):529-43
references.pmid: 8847645
references.citation: Genes Brain Behav. 2009 Oct;8(7):661-75
references.pmid: 19563516
references.citation: Neuropsychopharmacology. 2011 Jan;36(1):227-50
references.pmid: 20844477
references.citation: Schizophr Bull. 2000;26(1):119-36
references.pmid: 10755673
references.citation: Psychopharmacology (Berl). 2008 Aug;199(3):331-88
references.pmid: 18568339
references.citation: Neuron. 2007 Oct 4;56(1):33-42
references.pmid: 17920013
references.citation: J Neurosci. 2011 Oct 12;31(41):14677-87
references.pmid: 21994384
references.citation: Cereb Cortex. 2011 May;21(5):999-1011
references.pmid: 20843900
references.citation: Neuropharmacology. 2012 Mar;62(3):1504-18
references.pmid: 21349276
references.citation: Curr Opin Pharmacol. 2006 Feb;6(1):18-23
references.pmid: 16376150
references.citation: Curr Protoc Neurosci. 2001 May;Chapter 8:Unit 8.7
references.pmid: 18428548
references.citation: Curr Top Behav Neurosci. 2010;4:485-508
references.pmid: 21312410
references.citation: J Biol Chem. 2011 Dec 9;286(49):42105-42114
references.pmid: 22006921
references.citation: Neuropsychopharmacology. 2009 Feb;34(3):624-33
references.pmid: 18615011
references.citation: Am J Psychiatry. 2008 Dec;165(12):1585-93
references.pmid: 18923067
references.citation: Science. 2007 Oct 5;318(5847):71-6
references.pmid: 17823315
references.citation: Psychopharmacology (Berl). 2011 Feb;213(2-3):289-305
references.pmid: 21212939
references.citation: Nat Protoc. 2006;1(3):1117-9
references.pmid: 17406392
references.citation: Am J Psychiatry. 1999 Jul;156(7):1046-51
references.pmid: 10401450
references.citation: Biol Psychiatry. 2011 Mar 1;69(5):432-41
references.pmid: 21146155
references.citation: Behav Brain Res. 2011 Jan 20;216(2):481-95
references.pmid: 20816898
references.citation: Nat Protoc. 2006;1(1):7-12
references.pmid: 17406205
references.citation: Trends Neurosci. 2012 Jan;35(1):57-67
references.pmid: 22154068
references.citation: Nature. 2009 Jun 4;459(7247):698-702
references.pmid: 19396159