Constitutively active Rap2 transgenic mice display fewer dendritic spines, reduced extracellular signal-regulated kinase signaling, enhanced long-term depression, and impaired spatial learning and fear extinction.

Within the Ras superfamily of GTPases, Rap1 and Rap2 are the closest homologs to Ras. In non-neural cells, Rap signaling can antagonize Ras signaling. In neurons, Rap also seems to oppose Ras in terms of synaptic function. Whereas Ras is critical for long-term potentiation (LTP), Rap1 has been shown to be required for long-term depression (LTD), and Rap2 has been implicated in depotentiation. Moreover, active Rap1 and Rap2 cause loss of surface AMPA receptors and reduced miniature EPSC amplitude and frequency in cultured neurons. The role of Rap signaling in vivo, however, remains poorly understood. To study the function of Rap2 in the brain and in behavior, we created transgenic mice expressing either constitutively active (Rap2V12) or dominant-negative (Rap2N17) mutants of Rap2 in postnatal forebrain. Multiple lines of Rap2N17 mice showed only weak expression of the transgenic protein, and no phenotype was observed. Rap2V12 mice displayed fewer and shorter dendritic spines in CA1 hippocampal neurons, and enhanced LTD at CA3-CA1 synapses. Behaviorally, Rap2V12 mice showed impaired spatial learning and defective extinction of contextual fear, which correlated with reduced basal phosphorylation of extracellular signal-regulated kinase (ERK) and blunted activation of ERK during fear extinction training. Our data support the idea that Rap2 opposes Ras-ERK signaling in the brain, thereby inhibiting dendritic spine development/maintenance, promoting synaptic depression rather than LTP, and impairing learning. The findings also implicate Rap2 signaling in fear extinction mechanisms, which are thought to be aberrant in anxiety disorders and posttraumatic stress disorder.