# A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $89,416

## Abstract

Principal Investigator: Chen, Lu
Summary
 Our research focuses on uncovering the molecular mechanisms of a form of non-Hebbian synaptic
plasticity, namely homeostatic synaptic plasticity. In contrast to the self-reinforcing nature of Hebbian plasticity,
homeostatic plasticity operates under different rules as a “corrective” mechanism to prevent run-away Hebbian
plasticity. Compared to Hebbian plasticity, the molecular and cellular mechanisms underlying homeostatic
synaptic plasticity is much less understood, and their implication in neuropsychiatric disorders is largely
unexplored. Work from our labs in the past years show that retinoic acid (RA) signaling, a major signaling
pathway mediating homeostatic synaptic plasticity, is severely impaired in the absence of FMRP expression,
resulting in a lack of homeostatic plasticity in both mouse and human FXS neurons. Moreover, we demonstrate
that under a more natural, enriched environment, compromised homeostatic synaptic plasticity in adult mice
induces run away Hebbian plasticity as manifested by greatly enhanced LTP and diminished LTD. As a
behavioral consequence, animals with defective homeostatic plasticity exhibit enhanced learning but reduced
behavioral flexibility when raised in enriched environment. Together, our work establishes a link between
synaptic RA signaling, homeostatic plasticity and cognitive function, and suggests that impaired homeostatic
plasticity may contribute to cognitive deficits in FXS. The goal of the proposed research project in the parent
grant is to gain further understanding of the molecular and cellular mechanisms of RA-dependent homeostatic
plasticity in the mouse brain. The project proposed in this administrative supplement further extends the
experimental system to human neurons. Specifically, we will investigate whether aberrant alternative splicing of
Neurexin genes underlies homeostatic synaptic plasticity phenotype in the FXS. Using the human brain organoid
and assembloid models established in our lab, we will aim to validate in human neurons the findings from Specific
Aim 1 of the mouse studies.
PHS 398/2590 (Rev. 11/07) Page 1 Summary

## Key facts

- **NIH application ID:** 10841345
- **Project number:** 3R01NS115660-04S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Lu Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $89,416
- **Award type:** 3
- **Project period:** 2023-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841345

## Citation

> US National Institutes of Health, RePORTER application 10841345, A molecular investigation of retinoic acid-dependent homeostatic synaptic plasticity (3R01NS115660-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841345. Licensed CC0.

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