Mechanistic and translational medicine studies of brain neurophysiology and phenotypic heterogeneity in fragile X syndrome

The development of next-generation therapeutics (genomic, cellular, and small molecule) in Fragile X Syndrome (FXS) is hindered by three knowledge gaps: 1) poor understanding of the developmental trajectory of brain dysfunction, 2) limited ability to account for phenotypic heterogeneity, and 3) inadequate validation of how translational models represent the human condition. Our team, established over a decade ago, has developed a stakeholder-informed translational research program dedicated to understanding FXS brain physiology across cellular, circuit, and systems levels. Our previous Centers have led the field in establishing an empirical framework for characterizing shared electrophysiological biomarkers in adults with FXS and the Fmr1-/- knockout (KO) mouse. To address the present gaps, our team proposes to synchronize human pediatric and mouse developmental studies, leveraging recent discoveries and our well-established methods to establish translational parallels. The proposed work addresses key limitations our of previous work while directly addressing all three RFA-HD-25-002 specific points of interest: 1) development of translatable biomarkers, 2) resolving phenotypic heterogeneity, and 3) identification of novel mechanisms. The NIH Center mechanism provides an ideal platform for our “Cells to Circuits to Systems to Community” approach, marked by close collaboration with scientists and community stakeholders, and facilitating three linked projects that span patient-centered research to in vivo animal experiments to layer-specific micro-circuit physiology: Project 1 (Erickson/Schmitt, Cincinnati Children’s) will study FXS youth aged 2-17 years to determine age-related changes and developmental trajectory of translatable biomarkers in FXS using resting, evoked auditory, and cognitive paradigms and evaluate heterogeneity by considering the impact of sex, age, FMRP expression, and EEG signatures on cognitive deficits and drug response. Project 2 (Binder/Razak, UC Riverside) will study brain activity using surface multi-electrode array (MEA) and depth array in vivo electrophysiology in the Fmr1 KO mouse across developmental stages using resting and evoked auditory paradigms in parallel with human studies and examine novel mechanistic approaches to address circuit hyperexcitability using genetic models and pharmacologic probes impacting glutamate NMDA receptors GluN2C/D and T-type Ca+ channels. Project 3 (Huber/Gibson, UT Southwestern) will determine synaptic, cellular and microcircuit mechanisms by which GluN2C/D drives excitability of circuits and alterations in thalamic-driven laminar activity and synchrony as well as study the maturation of multi-site, network-level function in Fmr1 KO mice using tetrode-based in vivo recordings during cognitive paradigms used in human studies. Across Projects, phenotypic variability will be examined across a large sample of human participants, mouse background strain, sex, age and FMRP expression. This comprehensive approach aims to accelerate treatment discovery in FXS by providing a foundation informed by development, variability, and mechanistic insights to advance translational medicine goals in FXS. Project Number: 1P50HD118717-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Craig Erickson | Institution: CINCINNATI CHILDRENS HOSP MED CTR, CINCINNATI, OH | Award Amount: $1,940,677 | Activity Code: P50 | Study Section: Special Emphasis Panel[ZHD1 DSR-A (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11173946