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Summary: Aims: The G‐protein‐coupled estrogen receptor GPR30 (also referred to as GPER) has been implicated in the estrogenic regulation of hippocampal plasticity and spatial memory; however, the molecular mechanisms are largely unclear. Methods: In this study, we initially examined the levels of GPR30 in the hippocampus of postnatal, ovariectomy (OVX)‐ and letrozole (LET)‐treated female mice. Under G1, G15, and/or OVX treatment, the spatial memory, spine density, levels of ERα, ERβ, and SRC‐1, selected synaptic proteins, mTORC2 signals (Rictor and p‐AKT Ser473), and actin polymerization dynamics were subsequently evaluated. Furthermore, G1, G15, and/or E2 combined with SRC‐1 and/or PI3K inhibitors, actin cytoskeleton polymerization modulator JPK, and CytoD treatments were used to address the mechanisms that underlie GPR30 regulation in vitro. Finally, mTORC2 activator A‐443654 (A4) was used to explore the role of mTORC2 in GPR30 regulation of spatial memory. Results: The results showed that high levels of GPR30 were detected in the adult hippocampus and the levels were downregulated by OVX and LET. OVX induced an impairment of spatial memory, and changes in other parameters previously described were reversed by G1 and mimicked by G15. Furthermore, the E2 effects on SRC‐1 and mTORC2 signals, synaptic proteins, and actin polymerization were inhibited by G15, whereas G1 effects on these parameters were inhibited by the blockade of SRC‐1 or PI3K; the levels of synaptic proteins were regulated by JPK and CytoD. Importantly, G15‐induced actin depolymerization and spatial memory impairment were rescued by mTORC2 activation with A4. Conclusions: Taking together, these results demonstrated that decreased GPR30 induces actin depolymerization through SRC‐1 and PI3K/mTORC2 pathways and ultimately impairs learning and memory, indicating its potential role as a therapeutic target against hippocampus‐based, E2‐related memory impairments. [ABSTRACT FROM AUTHOR]

Summary: Aims: Estrogens play pivotal roles in hippocampal synaptic plasticity through nuclear receptors (nERs; including ERα and ERβ) and the membrane receptor (mER; also called GPR30), but the underlying mechanism and the contributions of nERs and mER remain unclear. Mammalian target of rapamycin complex 2 (mTORC2) is involved in actin cytoskeleton polymerization and long‐term memory, but whether mTORC2 is involved in the regulation of hippocampal synaptic plasticity by ERs is unclear. Methods: We treated animals with nER antagonists (MPP/PHTPP) or the mER antagonist (G15) alone or in combination with A‐443654, an activator of mTORC2. Then, we examined the changes in hippocampal SRC‐1 expression, mTORC2 signaling (rictor and phospho‐AKTSer473), actin polymerization (phospho‐cofilin and profilin‐1), synaptic protein expression (GluR1, PSD95, spinophilin, and synaptophysin), CA1 spine density, and synapse density. Results: All of the examined parameters except synaptophysin expression were significantly decreased by MPP/PHTPP and G15 treatment. MPP/PHTPP and G15 induced a similar decrease in most parameters except p‐cofilin, GluR1, and spinophilin expression. The ER antagonist‐induced decreases in these parameters were significantly reversed by mTORC2 activation, except for the change in SRC‐1, rictor, and synaptophysin expression. Conclusions: nERs and mER contribute similarly to the changes in proteins and structures associated with synaptic plasticity, and mTORC2 may be a novel target of hippocampal‐dependent dementia such as Alzheimer's disease as proposed by previous studies. [ABSTRACT FROM AUTHOR]