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

Abstract

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.

HDAC9‐mediated calmodulin deacetylation induces memory impairment in Alzheimer's disease

“… 28 In previous studies, we demonstrated that SRC3‐mediated CaM acetylation was important for CaMKIIα activity and hippocampus‐dependent memory in mice. 31 , 45 , 46 Here, we showed that HDAC9‐mediated CaM deacetylation and CaMKIIα activity are severely abnormal in AD mouse brain. In addition to CaMKIIα, CaM has many other target proteins, several of which have been implicated in synaptic plasticity, neurotransmission or neuronal excitability.…”

“…While total CaM, CaMKIIα, GluR1, and PSD95 did not change significantly in WT and APP/PS1 mice (Figure 2A,E–H,J,N–Q). In previous studies, we identified that SRC3 was the CaM acetyltransferase, and revealed that CaM acetylation was necessary for CaMKIIα activation 31,45,46 . We studied whether decreased CaM acetylation is caused by reduced SRC3, and found that SRC3 did not change significantly in APP/PS1 mice, compared to WT mice (Figure 2A,I,J,R).…”

“…28 In previous studies, we demonstrated that SRC3-mediated CaM acetylation was important for CaMKIIα activity and hippocampus-dependent memory in mice. 31,45,46 Here, we showed that HDAC9-mediated CaM deacetylation and CaMKIIα activity are severely abnormal in AD mouse brain.…”

“…In previous studies, we identified that SRC3 was the CaM acetyltransferase, and revealed that CaM acetylation was necessary for CaMKIIα activation. 31 , 45 , 46 We studied whether decreased CaM acetylation is caused by reduced SRC3, and found that SRC3 did not change significantly in APP/PS1 mice, compared to WT mice (Figure 2A,I,J,R ). This result perhaps suggests that decreased CaM acetylation may be due to elevated CaM deacetylase in APP/PS1 mice.…”

“…In previous studies, we identified that SRC3 was the CaM acetyltransferase, and revealed that CaM acetylation was necessary for CaMKIIα activation. 31,45,46 We studied whether decreased CaM acetylation is caused by reduced SRC3, and found that SRC3…”