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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 amygdala neural activation during fear conditioning. (a) Basolateral nucleus of the amygdala cFOS staining was significantly increased in HOM mice over WT at baseline (P<0.01). WT cFOS significantly increased after fear conditioning (P<0.05), but no other genotype had an increase in cFOS. Scale bar, 200 μm for all micrographs. (b) Lateral nucleus cFOS staining was significantly affected by fear conditioning (P<0.0001). Post hoc comparisons of genotype-specific effects within and between fear conditioning groups were not significant (P>0.05). (c) Central nucleus cFOS staining was not significantly affected by genotype or fear conditioning. *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.
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fig2: Rapgef6 deletion impairs amygdala neural activation during fear conditioning. (a) Basolateral nucleus of the amygdala cFOS staining was significantly increased in HOM mice over WT at baseline (P<0.01). WT cFOS significantly increased after fear conditioning (P<0.05), but no other genotype had an increase in cFOS. Scale bar, 200 μm for all micrographs. (b) Lateral nucleus cFOS staining was significantly affected by fear conditioning (P<0.0001). Post hoc comparisons of genotype-specific effects within and between fear conditioning groups were not significant (P>0.05). (c) Central nucleus cFOS staining was not significantly affected by genotype or fear conditioning. *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.

Mentions: In WT animals, cFOS expression was significantly affected by conditioning in the basolateral and lateral amygdala but not in the central amygdala (Figures 2a–c, N=3 mice and n=8 sections per mouse per genotype for all cFOS experiments, ANOVA, basolateral: F(5,271)=6.76, P<0.0001, lateral: F(5,272)=5.29, P=0.0001, central: F(5,265)=0.57, P=0.73). On post hoc testing, however, only in the basolateral amygdala was WT cFOS expression significantly increased in fear conditioned as compared with unconditioned WT animals (Bonferroni post hocP<0.0001); this was a trend in the lateral amygdala.


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 amygdala neural activation during fear conditioning. (a) Basolateral nucleus of the amygdala cFOS staining was significantly increased in HOM mice over WT at baseline (P<0.01). WT cFOS significantly increased after fear conditioning (P<0.05), but no other genotype had an increase in cFOS. Scale bar, 200 μm for all micrographs. (b) Lateral nucleus cFOS staining was significantly affected by fear conditioning (P<0.0001). Post hoc comparisons of genotype-specific effects within and between fear conditioning groups were not significant (P>0.05). (c) Central nucleus cFOS staining was not significantly affected by genotype or fear conditioning. *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

fig2: Rapgef6 deletion impairs amygdala neural activation during fear conditioning. (a) Basolateral nucleus of the amygdala cFOS staining was significantly increased in HOM mice over WT at baseline (P<0.01). WT cFOS significantly increased after fear conditioning (P<0.05), but no other genotype had an increase in cFOS. Scale bar, 200 μm for all micrographs. (b) Lateral nucleus cFOS staining was significantly affected by fear conditioning (P<0.0001). Post hoc comparisons of genotype-specific effects within and between fear conditioning groups were not significant (P>0.05). (c) Central nucleus cFOS staining was not significantly affected by genotype or fear conditioning. *P<0.05, **P<0.01 and ***P<0.001. HET, heterozygous; HOM, homozygous; WT, wild type.
Mentions: In WT animals, cFOS expression was significantly affected by conditioning in the basolateral and lateral amygdala but not in the central amygdala (Figures 2a–c, N=3 mice and n=8 sections per mouse per genotype for all cFOS experiments, ANOVA, basolateral: F(5,271)=6.76, P<0.0001, lateral: F(5,272)=5.29, P=0.0001, central: F(5,265)=0.57, P=0.73). On post hoc testing, however, only in the basolateral amygdala was WT cFOS expression significantly increased in fear conditioned as compared with unconditioned WT animals (Bonferroni post hocP<0.0001); this was a trend in the lateral amygdala.

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