# Network Mechanisms, Biomarkers and Pharmacology of Fragile X Syndrome in Humans

> **NIH NIH U54** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $376,445

## Abstract

Project 1 Abstract
Over the past 6 years, the human research component of our Fragile X Syndrome (FXS) Research Consortium
has established neurophysiological alterations linked to key sensory, cognitive, and symptom correlates in FXS.
We first reported cortical hyperexcitability in the form of excessive gamma power at rest and a reduced ability to
mount appropriate neural responses to auditory stimuli. We demonstrated that features are conserved in parallel
murine EEG experiments (Project 2 team) and probed further in ex vivo recordings within cortical slices in the
Fmr1 KO mouse (Project 3 team). Our established collaborations represent one of, if not the most tightly
integrated bench to bedside research programs studying FXS. Our central hypothesis posits that the absence of
fragile X mental retardation protein (FMRP) results in cortical hyperexcitability reflected in elevated background
gamma band power and altered cross-frequency regulatory processes. The overarching aims of Project 1 are
to better clarify the nature of neurophysiological alterations and their clinical implications using new paradigms
and analytic techniques, extend findings from sensory to association cortex, initiate EEG studies of cognitive and
behavioral processes, use our neurophysiological biomarkers to predict and track response to glutamatergic and
GABAergic drugs, and with large samples investigate heterogeneity in neurophysiological alterations related to
genetic and demographic features. We aim to pursue network neurophysiology modeling in adults with FXS,
typically developing and developmentally delayed matched control subjects. In this work we will evaluate
neurophysiology during cognitive processes that are altered in FXS. We will additionally develop integrated
modeling of neural oscillatory alterations across rest, during sensory processing and during cognitive activity.
We aim to conduct novel placebo-controlled, single-dose, crossover mechanistic drug challenge studies in adults
with FXS. This drug challenge will focus on small molecule targeting of GABAB neurotransmission (arbaclofen),
GABAA neurotransmission (BAER-101; formerly AZD7325), and NMDA glutamatergic neurotransmission
(memantine). We will evaluate drug impact on neurophysiology outcomes, behavior, and cognition in parallel
with testing of the same drugs in the Fmr1 KO mouse in Project 2. Third, we aim to resolve heterogeneity within
human FXS by evaluating neurophysiological, cognitive, and clinical profiles in humans with FXS based on sex,
mosaic status, and blood FMRP level. We will additionally evaluate age-related variability in neurophysiologic,
cognitive, and clinical profiles in a cross-sectional study of patients with FXS and healthy controls in the youth
age range. These efforts build on our experience to date moving forward FXS translational medicine efforts by
ensuring tight linkages to the experiments of our preclinical collaborators. This ensures that results of preclinical
work can ...

## Key facts

- **NIH application ID:** 10271298
- **Project number:** 5U54HD104461-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Craig Erickson
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,445
- **Award type:** 5
- **Project period:** 2020-09-25 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271298

## Citation

> US National Institutes of Health, RePORTER application 10271298, Network Mechanisms, Biomarkers and Pharmacology of Fragile X Syndrome in Humans (5U54HD104461-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10271298. Licensed CC0.

---

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