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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 contextual and cued fear conditioning, implying amygdala dysfunction. (a) Contextual fear conditioning had a significant effect of genotype (P=0.016) but not test time (P=0.09) with HOM mice freezing less in the original context at the second, fourth and fifth minutes (P<0.05). (b) Averaged contextual fear also had a significant effect of genotype (P=0.016), with HOM mice freezing significantly less than WT (P<0.05). (c) In the novel context, there was a significant effect of genotype (P=0.03) with HET and HOM mice freezing less than WT in the final minute (P<0.05). (d) Averaged novel context was also significantly affected by genotype (P=0.03) with no post hoc comparisons significant. (e) Cued fear conditioning had a significant effect of genotype (P=0.003). HOM mice froze less than WT at each time point (P<0.05). (f) Averaged cued fear was also significantly affected by genotype (P=0.003) with HOM mice freezing less than HET (P<0.05) and WT (P<0.01). *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.
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fig1: Rapgef6 deletion impairs contextual and cued fear conditioning, implying amygdala dysfunction. (a) Contextual fear conditioning had a significant effect of genotype (P=0.016) but not test time (P=0.09) with HOM mice freezing less in the original context at the second, fourth and fifth minutes (P<0.05). (b) Averaged contextual fear also had a significant effect of genotype (P=0.016), with HOM mice freezing significantly less than WT (P<0.05). (c) In the novel context, there was a significant effect of genotype (P=0.03) with HET and HOM mice freezing less than WT in the final minute (P<0.05). (d) Averaged novel context was also significantly affected by genotype (P=0.03) with no post hoc comparisons significant. (e) Cued fear conditioning had a significant effect of genotype (P=0.003). HOM mice froze less than WT at each time point (P<0.05). (f) Averaged cued fear was also significantly affected by genotype (P=0.003) with HOM mice freezing less than HET (P<0.05) and WT (P<0.01). *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.

Mentions: There were no significant differences between genotypes on baseline fear as measured by initial freezing response before tone-shock pairings or nociception as measured by freezing during the two delivered shocks (Supplementary Figure 3). HOM mice froze significantly less on contextual and cued fear conditioning, indicating widespread fear learning deficits. On contextual testing, HOM mice froze significantly less than WT littermates, suggesting impairment of the hippocampus and/or amygdala (Figure 1a, n=12 WT, 12 HET, 9 HOM mice for all fear experiments, repeated measures two-way ANOVA, effect of genotype, F(2,145)=4.78, P=0.016, Bonferroni post hocP<0.05 for WT vs HOM at the second, fourth and fifth minute; Figure 1b, ANOVA, F(2,29)=4.78, P=0.016, Bonferroni post hocP<0.05).


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 contextual and cued fear conditioning, implying amygdala dysfunction. (a) Contextual fear conditioning had a significant effect of genotype (P=0.016) but not test time (P=0.09) with HOM mice freezing less in the original context at the second, fourth and fifth minutes (P<0.05). (b) Averaged contextual fear also had a significant effect of genotype (P=0.016), with HOM mice freezing significantly less than WT (P<0.05). (c) In the novel context, there was a significant effect of genotype (P=0.03) with HET and HOM mice freezing less than WT in the final minute (P<0.05). (d) Averaged novel context was also significantly affected by genotype (P=0.03) with no post hoc comparisons significant. (e) Cued fear conditioning had a significant effect of genotype (P=0.003). HOM mice froze less than WT at each time point (P<0.05). (f) Averaged cued fear was also significantly affected by genotype (P=0.003) with HOM mice freezing less than HET (P<0.05) and WT (P<0.01). *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

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getmorefigures.php?uid=PMC4490285&req=5

fig1: Rapgef6 deletion impairs contextual and cued fear conditioning, implying amygdala dysfunction. (a) Contextual fear conditioning had a significant effect of genotype (P=0.016) but not test time (P=0.09) with HOM mice freezing less in the original context at the second, fourth and fifth minutes (P<0.05). (b) Averaged contextual fear also had a significant effect of genotype (P=0.016), with HOM mice freezing significantly less than WT (P<0.05). (c) In the novel context, there was a significant effect of genotype (P=0.03) with HET and HOM mice freezing less than WT in the final minute (P<0.05). (d) Averaged novel context was also significantly affected by genotype (P=0.03) with no post hoc comparisons significant. (e) Cued fear conditioning had a significant effect of genotype (P=0.003). HOM mice froze less than WT at each time point (P<0.05). (f) Averaged cued fear was also significantly affected by genotype (P=0.003) with HOM mice freezing less than HET (P<0.05) and WT (P<0.01). *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.
Mentions: There were no significant differences between genotypes on baseline fear as measured by initial freezing response before tone-shock pairings or nociception as measured by freezing during the two delivered shocks (Supplementary Figure 3). HOM mice froze significantly less on contextual and cued fear conditioning, indicating widespread fear learning deficits. On contextual testing, HOM mice froze significantly less than WT littermates, suggesting impairment of the hippocampus and/or amygdala (Figure 1a, n=12 WT, 12 HET, 9 HOM mice for all fear experiments, repeated measures two-way ANOVA, effect of genotype, F(2,145)=4.78, P=0.016, Bonferroni post hocP<0.05 for WT vs HOM at the second, fourth and fifth minute; Figure 1b, ANOVA, F(2,29)=4.78, P=0.016, Bonferroni post hocP<0.05).

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