# Estrogenic regulation of the hippocampal ubiquitin-proteasome system and its role in memory and structural plastcity

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN MILWAUKEE · 2024 · $491,056

## Abstract

Project Summary
Memory impairment is a defining characteristic of many neuropsychiatric disorders, however, an understanding
of the complex neural mechanisms regulating hippocampal memory formation remains elusive. The sex steroid
17β-estradiol (E2) is a powerful modulator of hippocampal plasticity and memory in both males and females,
however the neural mechanisms through which this occurs are poorly understood. Therefore, the long-term goal
of our research is to pinpoint the neural mechanisms through which E2 regulates hippocampal memory
consolidation in males and females. The overall objectives of this application are to determine the mechanisms
through which E2 regulates activity of the ubiquitin proteasome system (UPS) and the extent to which
proteasomal protein degradation contributes to estrogenic regulation of memory consolidation and hippocampal
dendritic spine density in both sexes. Although UPS-mediated protein degradation in the hippocampus is
essential for synaptic remodeling and memory consolidation, the role that UPS activity plays in mediating E2’s
modulatory effects on memory formation and spine remodeling in either sex remains completely unexplored. Our
central hypothesis is that UPS-mediated protein degradation in the DH is triggered by E2 acting at estrogen and
glutamate receptors and is a principal mechanism through which E2 promotes memory consolidation and CA1
spine density. This hypothesis is based on previous work suggesting overlapping mechanisms through which E2
and UPS activity contribute to hippocampal plasticity and memory. Our central hypothesis will be evaluated in
the following three specific aims: 1) determine the cellular mechanisms through which E2 activates hippocampal
UPS activity, 2) identify protein targets of E2-induced UPS activation across subcellular compartments, 3)
establish a key role for proteasome activity in E2-induced facilitation of memory consolidation and CA1 spine
density. Regionally- and temporally- specific pharmacological manipulations will be used to establish receptor
mechanisms underlying E2-UPS interactions in the dorsal hippocampus, as well as the structural and behavioral
outcomes of these interactions. Cutting edge ubiquitin-specific mass spectrometry-based proteomics will also be
used to identify novel proteins targeted by E2 for degradation. This work is innovative in that it represents a
fundamental shift from a conventional focus on protein synthesis as a primary contributor to estrogenic memory
modulation to a novel consideration of protein degradation as an equal and opposite counterpart necessary for
estrogenic regulation of hippocampal plasticity and memory. This contribution is significant because it will provide
essential foundational knowledge about the mechanisms through which E2 regulates memory consolidation in
both sexes, which could lead to the development of novel sex-specific treatments to address the memory
dysfunction observed in numerous mental disorders.

## Key facts

- **NIH application ID:** 10886815
- **Project number:** 5R01NS128123-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN MILWAUKEE
- **Principal Investigator:** Karyn M Frick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $491,056
- **Award type:** 5
- **Project period:** 2023-07-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886815

## Citation

> US National Institutes of Health, RePORTER application 10886815, Estrogenic regulation of the hippocampal ubiquitin-proteasome system and its role in memory and structural plastcity (5R01NS128123-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10886815. Licensed CC0.

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