# Defining Plasticity and Homeostasis in Fragile X Syndrome

> **NIH NIH R56** · UNIVERSITY OF COLORADO DENVER · 2021 · $439,297

## Abstract

Project Abstract
We propose to investigate circuit homeostasis in the developing amygdala in a mouse model of Fragile X
Syndrome (FXS) - a pervasive neurodevelopmental disorder (NDD) and a leading monogenic cause of
autism. Many NDDs, such as FXS, are characterized by age-dependent symptom onset and regression in
early life. Recent evidence, including our own publications, from monogenetic mouse models of NDDs reveal
that critical periods of synaptic plasticity are altered in terms of onset, duration and offset. This altered critical
period in NDDs is often referred to as a ‘sensitive time window’ – a time regulated window of synaptic
impairment. Therefore, the identification of sensitive time windows has implications for understanding brain
development and may indicate vulnerable periods for when therapeutic rescue is most effective.
We have identified a brief period of enhanced synaptic plasticity in the developing amygdala in the Fmr1
knock out (KO) mouse model of FXS (Vislay et al., JNeurosci 2013). This is akin to a sensitive time window
of plasticity in FXS. This discovery was built on our previous observation that inhibitory function is significantly
depleted in Fmr1 KOs from postnatal day (P)21) through adult ages. We asked the question, “Are inhibitory
circuits defective from birth or do they develop into defective circuits?”. Therefore, we examined the
development of inhibitory circuit function during the first three weeks of postnatal development. At P10, when
GABAA receptor mediated currents are inhibitory, Fmr1 KOs show decreased inhibitory function. However,
surprisingly we observe that there is a homeostatic correction of defective inhibition between P14-16. This
increase in inhibitory function is merely transient as this correction ultimately fails to be maintained by the P21
timepoint. By P21, synaptic inhibition falls below that of normal function through adulthood (Olmos-Serrano
et al., JNeurosci 2010, Martin et al., JNeurophysiol 2014). We propose this increase in inhibitory function may
be a “biomarker” for plasticity and thereby represents a sensitive time window in the developing fragile-x
amygdala.
In the present proposal, we will identify how this homeostatic fluctuation of inhibition occurs in Fmr1 KOs at
key timepoints. The collective goal of these experiments is to determine how fluctuations in inhibitory function
affect circuit function, structure, plasticity and behavior. In Specific Aim 1 we will explore this phenomenon
with a comprehensive plan of experiments that will first examine how inhibitory circuits are altered in terms of
function, connectivity and anatomy. In Specific Aim 2 we will determine how this period of homeostasis
affects circuit plasticity and specific behaviors in early postnatal development. In summary, our proposed
experiments will provide a clear identification of circuitry changes that alter the synaptic balance of developing
circuits in a behaviorally relevant brain region for NDDs.

## Key facts

- **NIH application ID:** 10418869
- **Project number:** 1R56MH127213-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** MOLLY-MAUREEN HUNTSMAN
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $439,297
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418869

## Citation

> US National Institutes of Health, RePORTER application 10418869, Defining Plasticity and Homeostasis in Fragile X Syndrome (1R56MH127213-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10418869. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*