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It is well established that steroids like androgen and estrogens regulate brain structure and function through their nuclear receptors,which need coactivators for their transcription activities.Steroid receptor coactivator-1(SRC-1)has been extensively localized in the brain of many animals including mice.Several clues have revealed the potential of SRC-1 in the regulation of hippocampal SRC-1 synaptic plasticity,but its exact role remains unclear.In this study,we provided direct evidences for the involvement of SRC-1 in hippocampal synaptic plasticity.Lentivirus containing shSRC-1 was stereotactically injected into CA1 of male mice for 2 weeks,levels of SRC-1 protein deceased by near 70%as shown by immunohistochemistry and Western blot.Morris water maze showed shSRC-1 animals had longer escape latency and worse spatial memory retention than control animals.Both immunohistochemistry and Western blot indicated that some key postsynaptic proteins including PSD-95,GluR1,as well as spine-synapse marker spinophilin but not presynaptic synaptophysin decreased dramatically.Interestingly,levels of androgen receptor,estrogen receptor α and β were also decreased significantly.Additionally,synapse density and the thickness of postsynaptic density(PSD)were also decreased significantly,too.The above results were further demonstrated by in vitro experiments using mice hippocampal cell lines mHippo-14,which expresses most of the neuronal markers,receptors as well as synaptic proteins as demonstrated by others and our experiments.In these cells,shSRC-1 not only decreased postsynaptic proteins but also decreased phospho-CREB(pCREB),immunoprecipitation indicated that SRC-1 could bind to pCREB.The above results for the first time clearly demonstrated that in the hippocampus,by recruiting pCREB,SRC-1 plays pivotal roles in the regulation of synaptic plasticity,and finally affects learning and memory.