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14-3-3 proteins are implicated in the regulation of synaptic functions based on a Drosophila mutant model and mammalian neuronal cultures.To study the role of 14-3-3 proteins in vivo, we have successfully created lines of transgenic mice which were considered a functional knockout through expressing a YFP fused peptide.Our behavioral studies show that one of the founder lines (132) that has broad hippocampal transgene expression displays impaired spatial learning and memory.Here we examined the hippocampal synaptic plasticity of this founder line using electrophysiological methods.We found that the long-term potentiation (LTP) in the CA3-CA1 connection was dramatically reduced in the 132 line compared to their wildtype littermates.To further investigate the underlying mechanism, we recorded from another founder line (142) that only has CA3 transgene expression and found that LTP was not significantly altered.Interestingly, the 142 line does not exhibit a deficit in hippocampal-dependent learning and memory tasks.These findings suggest that 14-3-3 proteins play an important role in regulating synaptic plasticity, likely through a postsynaptic mechanism.