title: Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice.
abstract: Mice that were rendered heterozygous for the γ2 subunit of GABAA receptors (γ2(+/-) 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 γ2(+/-) model thereby provides strong support for the GABAergic deficit hypothesis of major depressive disorder. Here we show that γ2(+/-) 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 γ2(+/-) 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 γ2(+/-) 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 γ2(+/-) mice. The data indicate increasing congruence of the GABAergic, glutamatergic, stress-based and neurotrophic deficit hypotheses of major depressive disorder.
authors.affiliation: 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.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Sahir
authors.affiliation: Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Shoko
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Luellen
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Earnheart
authors.affiliation: Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Rachnanjali
authors.initials: R
authors.lastname: Lal
authors.affiliation: 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.
authors.forename: Ju Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Luscher
mesh_terms: D000818:Animals; D001007:Anxiety / Q000473:pathology / Q000503:physiopathology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D003712:Dendrites / Q000473:pathology / Q000502:physiology*; D003863:Depression / Q000473:pathology / Q000503:physiopathology*; D003865:Major Depressive Disorder; D004195:Disease Models, Animal; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D057507:Mice, 129 Strain; D055495:Neurogenesis / Q000502:physiology; D010641:Phenotype; D011963:Receptors, GABA-A / Q000172:deficiency* / Q000235:genetics; D013569:Synapses / Q000473:pathology / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C546280:Gabrg2 protein, mouse; D011963:Receptors, GABA-A; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid
keywords: Animal model of anxious depression; Hippocampal synaptogenesis; Neurogenesis; Postnatal development; Synaptic spines
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