title: Distinct behavioral consequences of short-term and prolonged GABAergic depletion in prefrontal cortex and dorsal hippocampus.
abstract: GABAergic interneurons are essential for a functional equilibrium between excitatory and inhibitory impulses throughout the CNS. Disruption of this equilibrium can lead to various neurological or neuropsychiatric disorders such as epilepsy or schizophrenia. Schizophrenia itself is clinically defined by negative (e.g., depression) and positive (e.g., hallucinations) symptoms as well as cognitive dysfunction. GABAergic interneurons are proposed to play a central role in the etiology and progression of schizophrenia; however, the specific mechanisms and the time-line of symptom development as well as the distinct involvement of cortical and hippocampal GABAergic interneurons in the etiology of schizophrenia-related symptoms are still not conclusively resolved. Previous work demonstrated that GABAergic interneurons can be selectively depleted in adult mice by means of saporin-conjugated anti-vesicular GABA transporter antibodies (SAVAs) in vitro and in vivo. Given their involvement in schizophrenia-related disease etiology, we ablated GABAergic interneurons in the medial prefrontal cortex (mPFC) and dorsal hippocampus (dHPC) in adult male C57BL/6N mice. Subsequently we assessed alterations in anxiety, sensory processing, hyperactivity and cognition after long-term (>14 days) and short-term (<14 days) GABAergic depletion. Long-term GABAergic depletion in the mPFC resulted in a decrease in sensorimotor-gating and impairments in cognitive flexibility. Notably, the same treatment at the level of the dHPC completely abolished spatial learning capabilities. Short-term GABAergic depletion in the dHPC revealed a transient hyperactive phenotype as well as marked impairments regarding the acquisition of a spatial memory. In contrast, recall of a spatial memory was not affected by the same intervention. These findings emphasize the importance of functional local GABAergic networks for the encoding but not the recall of hippocampus-dependent spatial memories.
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Research Group "Neuronal Plasticity" Munich, Germany.
authors: Judith M
authors: JM
authors: Reichel
authors: Paul Flechsig Institute for Brain Research, University of Leipzig Leipzig, Germany.
authors: Sabine
authors: S
authors: Nissel
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Research Group "Neuronal Plasticity" Munich, Germany.
authors: Gabriela
authors: G
authors: Rogel-Salazar
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Research Group "Neuronal Plasticity" Munich, Germany.
authors: Anna
authors: A
authors: Mederer
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Research Group "Neuronal Plasticity" Munich, Germany.
authors: Karola
authors: K
authors: Käfer
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Research Group "Neuronal Plasticity" Munich, Germany.
authors: Benedikt T
authors: BT
authors: Bedenk
authors: Synaptic Systems GmbH Göttingen, Germany.
authors: Henrik
authors: H
authors: Martens
authors: Paul Flechsig Institute for Brain Research, University of Leipzig Leipzig, Germany.
authors: Rebecca
authors: R
authors: Anders
authors: Paul Flechsig Institute for Brain Research, University of Leipzig Leipzig, Germany ; Effigos AG Leipzig, Germany.
authors: Jens
authors: J
authors: Grosche
authors: Department of Neurology, University of Leipzig Leipzig, Germany.
authors: Dominik
authors: D
authors: Michalski
authors: Paul Flechsig Institute for Brain Research, University of Leipzig Leipzig, Germany.
authors: Wolfgang
authors: W
authors: Härtig
authors: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Research Group "Neuronal Plasticity" Munich, Germany.
authors: Carsten T
authors: CT
authors: Wotjak
keywords: GABA; cognition; hippocampus; hyperactivity; immunolesion; prefrontal cortex; schizophrenia
references: Behav Brain Res. 2009 Dec 28;205(2):544-9
references: 19703496
references: Curr Pharm Biotechnol. 2012 Jun;13(8):1587-94
references: 22283754
references: Trends Neurosci. 1992 Aug;15(8):285-90
references: 1384197
references: Physiol Behav. 2002 Dec;77(4-5):513-7
references: 12526992
references: Brain Res Brain Res Rev. 2000 Mar;31(2-3):270-6
references: 10719153
references: Int J Neuropsychopharmacol. 2014 Oct;17(10):1609-19
references: 24787547
references: Neurobiol Learn Mem. 2013 Nov;106:324-33
references: 23742919
references: Nat Rev Neurosci. 2004 May;5(5):361-72
references: 15100719
references: Neuron. 2012 Sep 20;75(6):951-62
references: 22998865
references: Neuron. 2012 Dec 20;76(6):1057-70
references: 23259943
references: J Neurosci. 2012 Feb 8;32(6):1989-2001
references: 22323713
references: Neuron. 2006 Oct 5;52(1):139-53
references: 17015232
references: Psychopharmacology (Berl). 1997 Jul;132(2):169-80
references: 9266614
references: Psychopharmacology (Berl). 2004 Jun;174(1):99-110
references: 15205881
references: Nat Rev Neurosci. 2004 Oct;5(10):793-807
references: 15378039
references: Aging Cell. 2009 Jun;8(3):339-42
references: 19245676
references: Front Behav Neurosci. 2014 Feb 28;8:63
references: 24616678
references: Hippocampus. 2013 Dec;23(12):1395-409
references: 23966340
references: Neural Plast. 2012;2012:892784
references: 22792496
references: J Neurosci Methods. 1984 May;11(1):47-60
references: 6471907
references: Nature. 2014 Apr 3;508(7494):S16-7
references: 24695330
references: Annu Rev Neurosci. 2011;34:389-412
references: 21692661
references: Learn Mem. 2010 Feb 26;17(3):155-60
references: 20189960
references: Genes Brain Behav. 2009 Oct;8(7):685-98
references: 19563475
references: Mol Psychiatry. 2005 Jan;10(1):27-39
references: 15340352
references: Trends Neurosci. 1998 Jul;21(7):273-8
references: 9683315
references: Behav Brain Res. 1993 Dec 31;59(1-2):175-91
references: 7908804
references: Int J Neuropsychopharmacol. 2007 Aug;10(4):513-36
references: 17313699
references: Neuropsychopharmacology. 2014 Sep;39(10):2473-84
references: 24784549
references: Nat Neurosci. 2012 Mar 25;15(5):793-802
references: 22446880
references: Behav Brain Res. 2002 Aug 21;134(1-2):49-57
references: 12191791
references: J Neurosci Methods. 2008 Jun 15;171(1):30-8
references: 18377997
references: Schizophr Bull. 1998;24(2):285-301
references: 9613626
references: Learn Mem. 2004 Nov-Dec;11(6):770-86
references: 15537742
references: Science. 1986 Feb 28;231(4741):995-7
references: 3945815
references: Brain Res. 2010 Sep 24;1353:145-51
references: 20647005
references: Front Behav Neurosci. 2013 Aug 15;7:103
references: 23966915
references: Curr Protoc Neurosci. 2007 Apr;Chapter 9:Unit 9.24
references: 18428667
references: Am J Psychiatry. 2004 Apr;161(4):742-4
references: 15056523
references: Front Integr Neurosci. 2012 Feb 27;6:8
references: 22375107
references: Neurosci Biobehav Rev. 2004 May;28(3):273-83
references: 15225971
references: Prog Brain Res. 1992;94:353-65
references: 1337615
references: Neurobiol Dis. 2013 May;53:36-48
references: 23201207
references: Neuroscience. 1993 Mar;53(2):367-78
references: 8098509
references: Ann Neurol. 2003;54 Suppl 6:S3-12
references: 12891648
references: Nat Rev Neurosci. 2008 Jan;9(1):46-56
references: 18073775
references: Brain Struct Funct. 2010 May;214(4):339-53
references: 20221886
references: Neuropsychopharmacology. 2000 Feb;22(2):108-24
references: 10649824
references: Neuropharmacology. 2012 Mar;62(3):1574-83
references: 21277876
references: Behav Brain Res. 2004 Jul 9;152(2):403-12
references: 15196809
references: Actas Esp Psiquiatr. 2014 Jul-Aug;42(4):185-95
references: 25017496
references: Nature. 2011 Jul 27;477(7363):171-8
references: 21796121
references: Proc Natl Acad Sci U S A. 2014 May 20;111(20):7450-5
references: 24794528
references: Int J Neuropsychopharmacol. 2002 Jun;5(2):159-79
references: 12135541
references: Schizophr Res. 2007 Jul;93(1-3):296-303
references: 17482797
references: Learn Mem. 2006 Nov-Dec;13(6):728-33
references: 17142302
references: Curr Opin Neurobiol. 2014 Jun;26:7-14
references: 24650498
references: Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13372-7
references: 11069288
references: J Neurosci. 1998 Sep 15;18(18):7535-42
references: 9736671
references: Crit Rev Neurobiol. 2000;14 (1):23-45
references: 11253954
references: Eur J Neurosci. 2006 Jan;23 (1):279-84
references: 16420437
references: Science. 1996 May 24;272(5265):1176-9
references: 8638163
references: Prog Neurobiol. 2002 Jun;67(2):161-72
references: 12126659
references: Learn Mem. 2008 Dec 30;16(1):38-45
references: 19117915
references: Front Integr Neurosci. 2012 May 03;6:17
references: 22563310
references: Hippocampus. 2010 Jul;20(7):829-40
references: 19655319
references: J Neurosci. 2007 Jan 24;27(4):840-4
references: 17251424
references: Hippocampus. 2000;10(3):213-25
references: 10902891
references: Neurobiol Learn Mem. 2014 Jan;107:65-78
references: 24246555
references: Front Behav Neurosci. 2014 Sep 10;8:319
references: 25309370
references: Nature. 2011 May 26;473(7348):514-8
references: 21532590
references: Brain Res. 1989 Aug 28;495(2):387-95
references: 2569920
references: Nat Neurosci. 2014 May;17(5):710-8
references: 24705183
references: Behav Brain Res. 2014 Feb 1;259:143-51
references: 24211452
references: Hippocampus. 1996;6(4):347-470
references: 8915675
references: PLoS One. 2012;7(7):e40555
references: 22792368
references: Front Behav Neurosci. 2012 Dec 27;6:87
references: 23293591
references: Schizophr Res. 2005 Jan 1;72(2-3):109-22
references: 15560956
references: Mol Psychiatry. 2002;7(10):1039-53
references: 12476318
references: J Neurosci. 2012 Jul 25;32(30):10211-25
references: 22836256
references: Curr Opin Neurobiol. 2000 Apr;10(2):205-10
references: 10753790
references: Neuroscience. 1996 Sep;74(2):331-9
references: 8865186
references: Nature. 2012 Mar 14;484(7392):62-8
references: 22419153
references: Neuron. 2012 Feb 23;73(4):789-802
references: 22365551
references: Nature. 2013 Dec 12;504(7479):272-6
references: 24336286
references: J Neurosci. 2008 Dec 3;28(49):13125-31
references: 19052203