RRC ID 77814
Author Levy RJ, Kvajo M, Li Y, Tsvetkov E, Dong W, Yoshikawa Y, Kataoka T, Bolshakov VY, Karayiorgou M, Gogos JA.
Title Deletion of Rapgef6, a candidate schizophrenia susceptibility gene, disrupts amygdala function in mice.
Journal Transl Psychiatry
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.
Volume 5(6)
Pages e577
Published 2015-6-9
DOI 10.1038/tp.2015.75
PII tp201575
PMID 26057047
PMC PMC4490285
MeSH Amygdala / physiopathology* Animals Anxiety / genetics* CA3 Region, Hippocampal / pathology Conditioning, Psychological* DNA Copy Number Variations Dendritic Spines / pathology* Fear* Guanine Nucleotide Exchange Factors / genetics* Hippocampus / pathology Hippocampus / physiopathology* Long-Term Potentiation / genetics Memory, Short-Term Mice Mice, Knockout Phosphorylation Prefrontal Cortex / physiopathology Proto-Oncogene Proteins c-fos / metabolism Pyramidal Cells / pathology* Schizophrenia / genetics* Spatial Memory
IF 5.28
Mice RBRC02699