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 be forward translated while in parallel our human findings can inform preclinical approaches to establish new therapeutic targets and novel biomarkers to speed drug discovery for FXS.
