Regulation of synaptic function by NMDA receptor/PSD-95/SPAL-1 complex

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In this study, we examined physiological roles of SPAL-1, a novel GAP for Rap-1/2, using SPAL-1-deficient mice. In particular, we focused on the significance of NMDA receptor/PSD-95/SPAL-1 interaction in synaptic plasticity.1. SPAL-1-deficient mice showed impaired spatial learning in Morris water maze test and decreased cued fear response in fear conditioning test. This finding suggests that SPAL-1 is involved in hippocampus- or amygdale-dependent memory formation.2. We found that conditioned eyeblink response is impaired in mice lacking SPAL-1, suggesting that functional link between SPAL-1 and NMDA receptors.3. Electrophysiological analysis using hippocampal slices revealed enhanced LTP in hippocampal CA1 region in SPAL-1-deficient mice.4. Electron microscopic analysis of brain sections revealed smaller spines and shorter PSD in mice lacking SPAL-1.5. We further investigated the behavioral characteristics of SPAL-1-deficient mice and found increased locomotor activity in the open-field test.