# Circuit Defects Underlying Sensory Hypersensitivity in Fragile X Syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $331,500

## Abstract

SUMMARY / ABSTRACT
We plan to investigate circuit defects underlying sensory hypersensitivity in Fragile X syndrome (FXS), the
most common inherited form of intellectual impairment and the most common single gene cause of autism. In
hyperarousal to sensory stimuli, affected individuals are deeply troubled by sounds, smells, sights, or touches
that seem normal to others. This leads to maladaptive behaviors, including avoidance responses, such as
tactile defensiveness. Virtually all individuals with FXS suffer from tactile defensiveness and Fmr1 knockout
(Fmr1-/-) mice, an animal model of FXS, exhibit clear signs of sensory hyperarousal. Elucidating the types of
circuit dysfunction that cause fragile X mice to interpret certain stimuli as aversive/threatening, and how this
eventually leads to an avoidance response, represents a major knowledge gap in FXS research. To address
this, we propose a novel symptom-to-circuit-to-neuron approach in the Fmr1-/- mouse model of FXS in order to
investigate disruptions at the circuit and single neuron levels that result in altered sensory processing. In a
recent study (He et al., J Neurosci, 2017), we demonstrated how, in response to repetitive tactile stimulation of
whiskers, Fmr1-/- mice display a sensory avoidance behavior analogous to tactile defensiveness in humans.
Using in vivo calcium imaging in somatosensory (S1) barrel cortex, we then showed that repetitive whisker
stimulation results in a gradual reduction in neuronal firing in 2-week-old and in adult wild-type (WT) mice, but
not in Fmr1-/- mice. Thus, one of the circuit defects that could explain tactile defensiveness in FXS is a loss of
neuronal adaptation in cortical neurons (simply put, neurons in S1 cortex of fragile X mice are not be able to
tune out persistent tactile stimuli). We now propose to test whether this loss of neuronal adaptation results
from a dysfunction in parvalbumin (PV) or somatostatin (SST) GABAergic interneurons in S1 cortex, and then
to delineate circuit alterations in brain regions that are both upstream or downstream from S1 cortex. These
studies will allow us to generate a more detailed wiring diagram of sensory hyperarousal in FXS, by examining
three stages of sensory processing: thalamus (input), cortex (integration), and amygdala (output). Throughout,
we will investigate whether manipulating neuronal activity at each of these stages of sensory processing might
ameliorate maladaptive behaviors associated with sensory hyperarousal in Fmr1-/- mice. Our experimental
design employs cutting edge techniques, including in vivo two-photon calcium imaging, silicon microprobes,
DREADDs, and Cre-Lox genetics, and seeks to address important knowledge gaps in FXS. Because many of
the signaling pathways that are dysregulated in FXS are also implicated in other neurodevelopmental
disorders, we believe that our unique symptomàcircuit approach has a very high significance and is likely to
be of broad importance to many types of autism a...

## Key facts

- **NIH application ID:** 9848561
- **Project number:** 5R01HD054453-12
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Carlos Portera-Cailliau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,500
- **Award type:** 5
- **Project period:** 2007-04-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9848561

## Citation

> US National Institutes of Health, RePORTER application 9848561, Circuit Defects Underlying Sensory Hypersensitivity in Fragile X Syndrome (5R01HD054453-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9848561. Licensed CC0.

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