# Defining sensitive time windows in Fmr1 knockout mice

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2021 · $18,757

## Abstract

PROJECT SUMMARY/ABSTRACT
Homeostatic plasticity is critical for controlling excitability and maintaining synaptic balance for normal circuit
development and function. This precise balance between excitation and inhibition (E/I) is essential for
maintaining homeostasis during normal development. However, in neurodevelopmental disorders (NDDs) the
timing and regulation of critical periods are altered in early postnatal development by aberrant E/I balance.
Alterations in cellular and synaptic development during critical periods of circuit formation manifest as the
temporal onset of cognitive and behavioral impairments observed in NDDs during the first years of life. Fragile
X Syndrome (FXS) is a NDD whose clinical symptomatology includes intellectual disabilities, autism spectrum
disorders (ASDs), hyperactivity, and fear and anxiety disorders. However, despite FXS being one of the most
well-studied genetically-defined NDDs, there are no currently approved or effective therapies targeted to
disease-specific pathophysiology. A critical barrier to the development of effective therapies may be
understanding not only how to treat, but when to treat. Thus, defining the synaptic basis of altered
critical periods, and how E/I balance affects circuit formation and plasticity in FXS will provide deeper
insights into the neurological consequences related to problems with development and maintenance
of synaptic function and may suggest new therapeutic strategies in humans.
 In our studies, we observe periods of homeostatic changes in inhibition in early postnatal development
of the amygdala in Fmr1 KO mice. Our published and preliminary data show decreased inhibitory function in
the Fmr1 KO mouse model of FXS at postnatal day 10 (P10)) followed by a brief period of enhanced inhibitory
function in the developing amygdala between P14-16. Ultimately, this enhanced inhibitory function fails to be
maintained and by P21 Fmr1 KO mice again exhibit decreased inhibitory function. This is akin to a sensitive
time window of plasticity in FXS.
 It is our hypothesis that this brief window of enhanced inhibitory function 1) may be a
homeostatic response to changes in excitatory neurotransmission and 2) may drive the precocious
emergence of fear-learning behaviors. This proposal will seek to understand the functional development of
microcircuits within the amygdala and determine if early life pharmacologic intervention can impact the
developmental emergence of amygdala-based behaviors.
 These studies represent a unique, high-impact investigation providing me with foundational training in
diverse fields such as NDDs, critical period plasticity, inhibitory interneuron biology, chemosensory systems,
and behavioral paradigms. Furthermore, this proposal has translational relevance for early-life intervention in
NDDs representing a novel evaluation of pharmacologic interventions which may affect critical period plasticity.

## Key facts

- **NIH application ID:** 10138331
- **Project number:** 1F31MH124277-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Matthew N Svalina
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $18,757
- **Award type:** 1
- **Project period:** 2020-11-20 → 2021-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138331

## Citation

> US National Institutes of Health, RePORTER application 10138331, Defining sensitive time windows in Fmr1 knockout mice (1F31MH124277-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10138331. Licensed CC0.

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