PMID- 25107590 OWN - NLM STAT- MEDLINE DCOM- 20151005 LR - 20211021 IS - 1873-7064 (Electronic) IS - 0028-3908 (Print) IS - 0028-3908 (Linking) VI - 88 DP - 2015 Jan TI - Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice. PG - 171-9 LID - S0028-3908(14)00281-0 [pii] LID - 10.1016/j.neuropharm.2014.07.019 [doi] AB - Mice that were rendered heterozygous for the gamma2 subunit of GABAA receptors (gamma2(+/-) mice) have been characterized extensively as a model for major depressive disorder. The phenotype of these mice includes behavior indicative of heightened anxiety, despair, and anhedonia, as well as defects in hippocampus-dependent pattern separation, HPA axis hyperactivity and increased responsiveness to antidepressant drugs. The gamma2(+/-) model thereby provides strong support for the GABAergic deficit hypothesis of major depressive disorder. Here we show that gamma2(+/-) mice additionally exhibit specific defects in late stage survival of adult-born hippocampal granule cells, including reduced complexity of dendritic arbors and impaired maturation of synaptic spines. Moreover, cortical gamma2(+/-) neurons cultured in vitro show marked deficits in GABAergic innervation selectively when grown under competitive conditions that may mimic the environment of adult-born hippocampal granule cells. Finally, brain extracts of gamma2(+/-) mice show a numerical but insignificant trend (p = 0.06) for transiently reduced expression of brain derived neurotrophic factor (BDNF) at three weeks of age, which might contribute to the previously reported developmental origin of the behavioral phenotype of gamma2(+/-) mice. The data indicate increasing congruence of the GABAergic, glutamatergic, stress-based and neurotrophic deficit hypotheses of major depressive disorder. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Ren, Zhen AU - Ren Z AD - Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA; Center for Molecular Investigation of Neurological Disorders, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA. FAU - Sahir, Nadia AU - Sahir N AD - Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA. FAU - Murakami, Shoko AU - Murakami S AD - Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA. FAU - Luellen, Beth A AU - Luellen BA AD - Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA. FAU - Earnheart, John C AU - Earnheart JC AD - Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA. FAU - Lal, Rachnanjali AU - Lal R AD - Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA. FAU - Kim, Ju Young AU - Kim JY AD - Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Song, Hongjun AU - Song H AD - Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. FAU - Luscher, Bernhard AU - Luscher B AD - Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA; Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA; Center for Molecular Investigation of Neurological Disorders, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA. Electronic address: BXL25@psu.edu. LA - eng GR - RC1 MH089111/MH/NIMH NIH HHS/United States GR - R37 NS047344/NS/NINDS NIH HHS/United States GR - R21 MH097247/MH/NIMH NIH HHS/United States GR - MH097247/MH/NIMH NIH HHS/United States GR - MH089111/MH/NIMH NIH HHS/United States GR - R01 MH099851/MH/NIMH NIH HHS/United States GR - MH099851/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 - 20140805 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Gabrg2 protein, mouse) RN - 0 (Receptors, GABA-A) RN - 3KX376GY7L (Glutamic Acid) RN - 56-12-2 (gamma-Aminobutyric Acid) SB - IM MH - Animals MH - Anxiety/pathology/*physiopathology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cells, Cultured MH - Cerebral Cortex/growth & development/pathology/physiopathology MH - Dendrites/pathology/*physiology MH - Depression/pathology/*physiopathology MH - Depressive Disorder, Major MH - Disease Models, Animal MH - Female MH - Glutamic Acid/metabolism MH - Hippocampus/growth & development/pathology/physiopathology MH - Mice, 129 Strain MH - Neurogenesis/physiology MH - Phenotype MH - Receptors, GABA-A/*deficiency/genetics MH - Synapses/pathology/*physiology MH - gamma-Aminobutyric Acid/metabolism PMC - PMC4252742 MID - NIHMS619510 OTO - NOTNLM OT - Animal model of anxious depression OT - Hippocampal synaptogenesis OT - Neurogenesis OT - Postnatal development OT - Synaptic spines EDAT- 2014/08/12 06:00 MHDA- 2015/10/06 06:00 PMCR- 2016/01/01 CRDT- 2014/08/10 06:00 PHST- 2014/05/22 00:00 [received] PHST- 2014/07/08 00:00 [revised] PHST- 2014/07/21 00:00 [accepted] PHST- 2014/08/10 06:00 [entrez] PHST- 2014/08/12 06:00 [pubmed] PHST- 2015/10/06 06:00 [medline] PHST- 2016/01/01 00:00 [pmc-release] AID - S0028-3908(14)00281-0 [pii] AID - 10.1016/j.neuropharm.2014.07.019 [doi] PST - ppublish SO - Neuropharmacology. 2015 Jan;88:171-9. doi: 10.1016/j.neuropharm.2014.07.019. Epub 2014 Aug 5.