Steroid Receptor Coactivator 3 Regulates Synaptic Plasticity and Hippocampus-dependent Memory

Hai-Long Zhang1 • Bing Zhao2 • Pin Yang1 • Yin-Quan Du1 • Wei Han1 • Jianming Xu3 • Dong-Min Yin1
1 Key Laboratory of Brain Functional Genomics, Ministry of Education and Shanghai, School of Life Science, East China Normal University, Shanghai 200062, China 
2 MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Fudan University, Shanghai 200032, China 
3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
Steroid hormones play important roles in brain development and function. The signaling of steroid hormones depends on the interaction between steroid receptors and their coactivators. Although the function of steroid receptor coactivators has been extensively studied in other tissues, their functions in the central nervous system are less well investigated. In this study, we addressed the function of steroid receptor coactivator 3 (SRC3) – a member of the p160 SRC protein family that is expressed predominantly in the hippocampus. While hippocampal development was not altered in Src3+/− mice, hippocampus-dependent functions such as short-term memory and spatial memory were impaired. We further demonstrated that the deficient learning and memory in Src3+/− mice was strongly associated with the impairment of long-term potentiation (LTP) at Schaffer Collateral-CA1 synapses. Mechanistic studies indicated that Src3+/− mutation altered the composition of N-methyl-D-aspartate receptor subunits in the postsynaptic densities of hippocampal neurons. Finally, we showed that SRC3 regulated synaptic plasticity and learning mainly dependent on its lysine acetyltransferase activity. Taken together, these results reveal previously unknown functions of SRC3 in the hippocampus and thus may provide insight into how steroid hormones regulate brain function.
SRC3;  Steroid receptor; Synaptic plasticity; Learning and memory;  Hippocampus;  N-Methyl-Daspartate receptor