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Deletion of Rapgef6, a candidate schizophrenia susceptibility gene, disrupts amygdala function in mice.

Levy RJ, Kvajo M, Li Y, Tsvetkov E, Dong W, Yoshikawa Y, Kataoka T, Bolshakov VY, Karayiorgou M, Gogos JA - Transl Psychiatry (2015)

Bottom Line: 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.Electrophysiological analysis showed enhanced long-term potentiation at cortico-amygdala synapses.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Columbia University, New York, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Rapgef6 deletion impairs hippocampal neural activation during fear conditioning. (a) Dentate gyrus subregion of the hippocampus had reduced cFOS staining in HOM mice compared with WT at baseline (P<0.01) and after fear conditioning (P<0.05). Scale bar, 200 μm for all micrographs. (b) CA3 cFOS staining was increased in WT mice after fear conditioning (P<0.01) but not HET or HOM mice. (c) CA1 cFOS staining was increased in WT mice after fear conditioning (P<0.05) but not HET or HOM mice. *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.
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fig3: Rapgef6 deletion impairs hippocampal neural activation during fear conditioning. (a) Dentate gyrus subregion of the hippocampus had reduced cFOS staining in HOM mice compared with WT at baseline (P<0.01) and after fear conditioning (P<0.05). Scale bar, 200 μm for all micrographs. (b) CA3 cFOS staining was increased in WT mice after fear conditioning (P<0.01) but not HET or HOM mice. (c) CA1 cFOS staining was increased in WT mice after fear conditioning (P<0.05) but not HET or HOM mice. *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.

Mentions: In the hippocampus, WT cFOS staining levels in the dentate gyrus, CA3 and CA1 regions were all significantly affected by conditioning (Figures 3a–c, ANOVA, DG: F(5,222)=9.13, P<0.0001, CA3: F(5,223)=4.72, P=0.0004, CA1: F(5,220)=2.63, P=0.02). There was significantly increased cFOS in WT fear-conditioned mice in areas CA3 and CA1 (Bonferroni post hocP<0.01, P<0.05, respectively vs unconditioned). These results suggest fear conditioning specifically increases cFOS activation in many subnuclei of the amygdala and hippocampus within our protocol.


Deletion of Rapgef6, a candidate schizophrenia susceptibility gene, disrupts amygdala function in mice.

Levy RJ, Kvajo M, Li Y, Tsvetkov E, Dong W, Yoshikawa Y, Kataoka T, Bolshakov VY, Karayiorgou M, Gogos JA - Transl Psychiatry (2015)

Rapgef6 deletion impairs hippocampal neural activation during fear conditioning. (a) Dentate gyrus subregion of the hippocampus had reduced cFOS staining in HOM mice compared with WT at baseline (P<0.01) and after fear conditioning (P<0.05). Scale bar, 200 μm for all micrographs. (b) CA3 cFOS staining was increased in WT mice after fear conditioning (P<0.01) but not HET or HOM mice. (c) CA1 cFOS staining was increased in WT mice after fear conditioning (P<0.05) but not HET or HOM mice. *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490285&req=5

fig3: Rapgef6 deletion impairs hippocampal neural activation during fear conditioning. (a) Dentate gyrus subregion of the hippocampus had reduced cFOS staining in HOM mice compared with WT at baseline (P<0.01) and after fear conditioning (P<0.05). Scale bar, 200 μm for all micrographs. (b) CA3 cFOS staining was increased in WT mice after fear conditioning (P<0.01) but not HET or HOM mice. (c) CA1 cFOS staining was increased in WT mice after fear conditioning (P<0.05) but not HET or HOM mice. *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.
Mentions: In the hippocampus, WT cFOS staining levels in the dentate gyrus, CA3 and CA1 regions were all significantly affected by conditioning (Figures 3a–c, ANOVA, DG: F(5,222)=9.13, P<0.0001, CA3: F(5,223)=4.72, P=0.0004, CA1: F(5,220)=2.63, P=0.02). There was significantly increased cFOS in WT fear-conditioned mice in areas CA3 and CA1 (Bonferroni post hocP<0.01, P<0.05, respectively vs unconditioned). These results suggest fear conditioning specifically increases cFOS activation in many subnuclei of the amygdala and hippocampus within our protocol.

Bottom Line: 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.Electrophysiological analysis showed enhanced long-term potentiation at cortico-amygdala synapses.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Columbia University, New York, NY, USA.

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.

No MeSH data available.


Related in: MedlinePlus