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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.
Highlights
Recent genetic advances demonstrated that there is a shared genetic diathesis among neuropsychiatric disorders.[1]
Single-nucleotide polymorphism genotyping demonstrated association with a block of linkage disequilibrium including RAPGEF6.14–16 Considering overlap with other psychiatric diseases, anxiety and depression are associated with single-nucleotide polymorphisms in RAPGEF3 while RAPGEF4 single-nucleotide polymorphisms were associated with autism risk.[18]
Glutamatergic synaptic transmission in the cortico–amygdala projections is normal in Rapgef6−/− mice As auditory fear conditioning was impaired in Rapgef6−/− mice, we explored the effects of Rapgef[6] ablation on excitatory synaptic transmission in projections to the lateral nucleus of the amygdala (LA) from the auditory thalamus and auditory cortex, which deliver the conditioned stimulus (CS) information to the amygdala during both the acquisition and retrieval of conditioned fear memory.[51]
Summary
Recent genetic advances demonstrated that there is a shared genetic diathesis among neuropsychiatric disorders.[1]. Genetic data from a variety of schizophrenia studies converge onto the RAPGEF6 locus. RAPGEF6 was part of a large deletion associated with schizophrenia and mental retardation in a single patient,[5] and the 5q31.1 locus around this gene is the fourth most important schizophrenia linkage peak.[6,7,8,9,10,11,12,13] single-nucleotide polymorphism genotyping demonstrated association with a block of linkage disequilibrium including RAPGEF6.14–16 Considering overlap with other psychiatric diseases, anxiety and depression are associated with single-nucleotide polymorphisms in RAPGEF3 As Rapgef[6] is both a plausible functional and genetic candidate for schizophrenia risk, we performed a comprehensive analysis of mice lacking Rapgef[6] to uncover its role in synaptic plasticity and behavioral paradigms dependent on learning, as well as neurite architecture. Rapgef[6] affects cortico–amygdala long-term potentiation (LTP) and CA3 hippocampal spine density
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