title: Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine Treatment.
abstract: Major depressive disorder is increasingly recognized to involve functional deficits in both gamma-aminobutyric acid (GABA)ergic and glutamatergic synaptic transmission. To elucidate the relationship between these phenotypes, we used GABAA receptor γ2 subunit heterozygous (γ2(+/-)) mice, which we previously characterized as a model animal with construct, face, and predictive validity for major depressive disorder.
  
  
  
  To assess possible consequences of GABAergic deficits on glutamatergic transmission, we quantitated the cell surface expression of N-methyl-D-aspartate (NMDA)-type and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors and the function of synapses in the hippocampus and medial prefrontal cortex of γ2(+/-) mice. We also analyzed the effects of an acute dose of the experimental antidepressant ketamine on all these parameters in γ2(+/-) versus wild-type mice.
  
  
  
  Modest defects in GABAergic synaptic transmission of γ2(+/-) mice resulted in a strikingly prominent homeostatic-like reduction in the cell surface expression of NMDA-type and AMPA-type glutamate receptors, along with prominent functional impairment of glutamatergic synapses in the hippocampus and medial prefrontal cortex. A single subanesthetic dose of ketamine normalized glutamate receptor expression and synaptic function of γ2(+/-) mice to wild-type levels for a prolonged period, along with antidepressant-like behavioral consequences selectively in γ2(+/-) mice. The GABAergic synapses of γ2(+/-) mice were potentiated by ketamine in parallel but only in the medial prefrontal cortex.
  
  
  
  Depressive-like brain states that are caused by GABAergic deficits involve a homeostatic-like reduction of glutamatergic transmission that is reversible by an acute, subanesthetic dose of ketamine, along with regionally selective potentiation of GABAergic synapses. The data merge the GABAergic and glutamatergic deficit hypotheses of major depressive disorder.
authors.affiliation: Departments of Biology, Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Center for Research in Neuroscience (HP, DS), McGill University, Montreal General Hospital, Montreal, Quebec, Canada.
authors.forename: Horia
authors.initials: H
authors.lastname: Pribiag
authors.affiliation: Departments of Biology, Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Jefferson
authors.affiliation: Departments of Biology, Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Matthew
authors.initials: M
authors.lastname: Shorey
authors.affiliation: Departments of Biology, Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuchs
authors.affiliation: Center for Research in Neuroscience (HP, DS), McGill University, Montreal General Hospital, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Stellwagen
authors.affiliation: Departments of Biology, Pennsylvania State University, University Park, Pennsylvania; Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania; Center for Molecular Investigation of Neurological Disorders, Pennsylvania State University, University Park, Pennsylvania. Electronic address: BXL25@psu.edu.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Luscher
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology*; D015536:Down-Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C546280:Gabrg2 protein, mouse; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007649:Ketamine
keywords: Antidepressant drug mechanisms; GABA; Glutamate; Homeostatic synaptic plasticity; Major depressive disorder; Neuroligin