| Abstract |
In human genetic studies ofschizophrenia, we uncovered copy-number variants inRAPGEF6and RAPGEF2 genes. To discern the effects ofRAPGEF6deletion in humans, we investigated the behavior and neural functions of a mouse lackingRAPGEF6.RAPGEF6deletion 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.RAPGEF6deletion mice were most impaired in hippocampal and amygdalar function, brain regions implicated inschizophreniapathophysiology. The results provide a deeper understanding of the role of the amygdala inschizophreniaand suggest thatRAPGEF6may be a novel therapeutic target inschizophrenia. |