title: Deletion of Rapgef6, a candidate schizophrenia susceptibility gene, disrupts amygdala function in mice.
abstract: In human genetic studies of schizophrenia, we uncovered copy-number variants in RAPGEF6 and RAPGEF2 genes. To discern the effects of RAPGEF6 deletion in humans, we investigated the behavior and neural functions of a mouse lacking Rapgef6. Rapgef6 deletion resulted in impaired amygdala function measured as reduced fear conditioning and anxiolysis. Hippocampal-dependent spatial memory and prefrontal cortex-dependent working memory tasks were intact. Neural activation measured by cFOS phosphorylation demonstrated a reduction in hippocampal and amygdala activation after fear conditioning, while neural morphology assessment uncovered reduced spine density and primary dendrite number in pyramidal neurons of the CA3 hippocampal region of knockout mice. Electrophysiological analysis showed enhanced long-term potentiation at cortico-amygdala synapses. Rapgef6 deletion mice were most impaired in hippocampal and amygdalar function, brain regions implicated in schizophrenia pathophysiology. The results provide a deeper understanding of the role of the amygdala in schizophrenia and suggest that RAPGEF6 may be a novel therapeutic target in schizophrenia.
authors.affiliation: Department of Neuroscience, Columbia University, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Levy
authors.affiliation: 1] Department of Physiology and Cellular Biology, Columbia University, New York, NY, USA [2] Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kvajo
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Tsvetkov
authors.affiliation: Department of Otolaryngology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Dong
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshikawa
authors.affiliation: Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kataoka
authors.affiliation: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
authors.forename: V Y
authors.initials: VY
authors.lastname: Bolshakov
authors.affiliation: Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Karayiorgou
authors.affiliation: 1] Department of Neuroscience, Columbia University, New York, NY, USA [2] Department of Physiology and Cellular Biology, Columbia University, New York, NY, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Gogos
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D056654:CA3 Region, Hippocampal / Q000473:pathology; D003213:Conditioning, Psychological; D056915:DNA Copy Number Variations; D049229:Dendritic Spines / Q000473:pathology*; D005239:Fear; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000235:genetics; D008570:Memory, Short-Term; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017966:Pyramidal Cells / Q000473:pathology*; D012559:Schizophrenia / Q000235:genetics*; D065852:Spatial Memory
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D016760:Proto-Oncogene Proteins c-fos; C588099:Rapgef6 protein, mouse