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.
Highlights
Steroid hormones and their receptors play important roles in brain development and function [1], and steroid receptors act in a classic genomic signaling pathway to bind with target DNA and alter gene transcription [2]
Given that the NR2B subunit of the N-methyl-D-aspartate receptor (NMDAR) is required for long-term potentiation (LTP) while the NR2A subunit inhibits LTP [34], our results suggest that the alteration of NMDAR subunits in the postsynaptic density (PSD) fraction are responsible for the LTP deficits in the
LTP at Schaffer collaterals (SCs)-CA1 synapses is coupled to hippocampusdependent learning and memory [21, 35,36,37,38], we investigated whether steroid receptor coactivator 3 (SRC3) is important for these processes
Summary
Steroid hormones and their receptors play important roles in brain development and function [1], and steroid receptors act in a classic genomic signaling pathway to bind with target DNA and alter gene transcription [2]. These receptors can act in a rapid, non-genomic manner to activate intracellular signaling pathways [3]. The SRC family of p160 proteins consists of SRC1, SRC2, and SRC3 These coactivators physically interact with steroid receptors, including androgen, progesterone, and estrogen receptors as well as receptors for glucocorticoids, in a ligand-dependent manner [12,13,14]. SRC1 and SRC2 are widely expressed in several brain regions such as the cortex, hippocampus, amygdala, cerebellum, and hypothalamus [15, 16]; they have been shown to regulate a variety of brain functions such as sexual behaviors [17, 18], energy homeostasis [19, 20], learning and memory [21, 22], and the motor function of the cerebellum
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