Estradiol-dependent memory and hippocampal spine remodeling require proteasomal protein degradation

Although 17β-estradiol (E 2 ) is a critical neuromodulator of hippocampus-dependent memory and synaptic plasticity, the molecular mechanisms underlying these effects remain incompletely understood. Previous studies showed that E 2 enhances dorsal hippocampus-dependent memory consolidation by activating signaling pathways that promote protein synthesis and dendritic spine formation. However, these studies largely overlooked the contribution of protein degradation mediated by the ubiquitin proteasome system (UPS), despite extensive evidence implicating UPS activity in long-term memory and synaptic plasticity. Here, we combined temporally specific dorsal hippocampal infusions of the proteasome inhibitor β-lactone with three-dimensional spine morphometry to examine the role of UPS-mediated protein degradation in E 2 -induced memory consolidation and CA1 spinogenesis. Immediate post-training bilateral infusion of β-lactone into the dorsal hippocampus of ovariectomized female mice blocked E 2 -induced enhancement of object recognition memory and attenuated E 2 -associated improvements in spatial memory. Arbor-wide Golgi-based analyses revealed robust E 2 -induced increases in spine number across the apical dendritic tree and smaller parallel effects within the basal arbor. Segment-level analyses showed that E 2 produced the greatest structural changes on tertiary apical dendritic segments, increasing total, mushroom, and thin spine density and enhancing multiple morphometric features, including mushroom spine surface area and head-to-neck ratio. Secondary basal dendritic segments exhibited smaller, more variable changes. Many E 2 -associated structural effects were attenuated or abolished by β-lactone. Together, these findings provide the first evidence that proteasomal protein degradation contributes to estrogenic enhancement of hippocampus-dependent memory and CA1 dendritic spine remodeling, identifying UPS-mediated protein degradation as a previously unrecognized mechanism regulating estrogenic memory consolidation and structural plasticity. Significance Statement 17β-estradiol (E 2 ) rapidly enhances hippocampal memory consolidation and promotes CA1 dendritic spinogenesis, yet the molecular mechanisms that support these effects remain unclear. Here, we combine temporally specific dorsal hippocampal proteasome inhibition with three-dimensional Golgi-based spine analyses to show that proteasomal protein degradation is required for E 2 -induced enhancement of object recognition memory and contributes to E 2 -associated improvements in spatial memory in ovariectomized female mice. We further demonstrate that proteasome activity contributes to E 2 -induced increases in apical CA1 spine density and morphology. These findings reveal new insights into estrogenic modulation of cognition that may provide novel protein targets whose levels could be regulated to reduce memory dysfunction related to menopause, depression, and other conditions for which women are at greater risk.