Nuclear and membrane estrogen receptor antagonists induce similar mTORC2 activation‐reversible changes in synaptic protein expression and actin polymerization in the mouse hippocampus

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.