Letrozole induces worse hippocampal synaptic and dendritic changes and spatial memory impairment than ovariectomy in adult female mice

Estrogens (E2) derived from ovaries and/or local de novo synthesis in the hippocampus profoundly regulate hippocampal structure and function, but the importance of local E2 versus ovarian E2 on hippocampal synaptic plasticity and spatial memory has not been well elucidated. The present study used ovariectomy (OVX) and intraperitoneal injection of an E2 synthase inhibitor, letrozole (LET), in adult female mice to investigate changes in hippocampal steroid receptor coactivator-1 (SRC-1), postsynaptic proteins, and actin polymerization dynamics with these treatments. Changes in the CA1 spine density, synapse density and spatial learning and memory after OVX and LET were also investigated. As a result, OVX and LET showed similar regulation of the expression of GluR1, spinophilin and p-Cofilin, but LET tended to induce more significant changes in SRC-1, PSD95, Rictor, Cofilin and actin depolymerization. More significant decreases in F-actin/G-actin, CA1 spine density and synapse density were also observed after LET than after OVX. Notably, LET-treated mice showed worse learning and memory impairment than OVX mice. Taken together, these results demonstrated that circulating E2 played a limited role and that hippocampus-derived E2 played a more important role in the regulation of hippocampal synaptic plasticity and hippocampus-based spatial learning and memory.