Abstract
Sex steroid hormones such as 17β-estradiol (E2) are critical neuromodulators of hippocampal synaptic plasticity and hippocampus-dependent memory in both males and females. However, the mechanisms through which E2 regulates memory formation in both sexes remain unclear. Research to date suggests that E2 regulates hippocampus-dependent memory by activating numerous cell-signaling cascades to promote the synthesis of proteins that support structural changes at hippocampal synapses. However, this work has largely overlooked the equally important contributions of protein degradation mediated by the ubiquitin proteasome system (UPS) in remodeling the synapse. Despite being critically implicated in synaptic plasticity and successful formation of long-term memories, it remains unclear whether protein degradation mediated by the UPS is necessary for E2 to exert its beneficial effects on hippocampal plasticity and memory formation. The present article provides an overview of the receptor and signaling mechanisms so far identified as critical for regulating hippocampal E2 and UPS function in males and females, with a particular emphasis on the ways in which these mechanisms overlap to support structural integrity and protein composition of hippocampal synapses. We argue that the high degree of correspondence between E2 and UPS activity warrants additional study to examine the contributions of ubiquitin-mediated protein degradation in regulating the effects of sex steroid hormones on cognition.
Highlights
The sex steroid hormone 17β-estradiol (E2) is the most potent and prevalent circulating estrogen and has been studied extensively in the field of hormones and cognition because of its ability to regulate hippocampal synaptic plasticity, spinogenesis, and the storage of long-term memories in males and females
We have proposed that ubiquitin proteasome system (UPS)-mediated protein degradation is required for the E2-induced facilitation of cornu ammonis 1 (CA1) spine density and memory consolidation in both sexes, we suspect that the signaling mechanisms that regulate this activity may differ considerably between males and females
This review has summarized evidence suggesting that protein degradation is an important regulator of synaptic plasticity and memory (Kaang and Choi, 2012; Hegde, 2017), yet the role that UPS-mediated protein degradation plays in regulating E2’s modulatory effects on memory formation in either sex remains unexplored
Summary
The sex steroid hormone 17β-estradiol (E2) is the most potent and prevalent circulating estrogen and has been studied extensively in the field of hormones and cognition because of its ability to regulate hippocampal synaptic plasticity, spinogenesis, and the storage of long-term memories in males and females. It should be noted that one recent study using knock-in mouse models to block or mimic Rpt activity indicated no involvement in measures of plasticity, spine growth, or fear conditioning (Scudder et al, 2021), compensatory mechanisms may have mitigated the loss of a functional Rpt Ser120 subunit (Lokireddy et al, 2015; Guo et al, 2016) Overall, these findings suggest that CaMKIIα-dependent phosphorylation of Rpt may be critical for regulating the proteasomal protein degradation involved in synaptic remodeling and long-term memory. The first study to examine putative sex differences in UPS activity related to memory showed that CaMKII and PKA differentially regulate proteasome activity in male and female rats across subcellular compartments following contextual fear conditioning (Devulapalli et al, 2019) Tissue in these studies was fractionated to isolate synaptic, cytosolic, nuclear compartments. Based largely on circumstantial evidence from the E2 and UPS literatures, our model provides a framework to empirically test the roles of several UPS mechanisms in the effects of E2 on memory in both sexes across multiple brain regions and subcellular sites
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