SEX-DEPENDENT HYPOEXCITABILITY IN THE VISUAL THALAMUS OF A FRAGILE-X SYNDROME MOUSE MODEL

Fragile X Syndrome (FXS) is the leading cause of intellectual disability and autism spectrum disorders (ASDs). Some of the main symptoms include impaired sensory information processing which hinders quality-of-life, learning, and mood. Previous studies have shown this occurs through increased excitability of cortical neurons in sensory areas. However, the role of the thalamus, which provides major inputs to sensory areas has received less attention. Using patch-clamp electrophysiology in a FXS mouse model, our preliminary findings reveal a previously unrecognized thalamic dysfunction characterized by reduced excitability of thalamic relay neurons in a sex-specific manner. In females, there is reduction in membrane resistance and increase in inhibitory charge transfer, whereas in males, there is a reduction in the maximum firing frequency. These data suggest that excessive inhibition arising from local interneurons suppresses thalamic output, fundamentally altering sensory information flow to the cortex. Importantly, pharmacological suppression of these interneurons restores thalamic excitability to physiological levels, uncovering a novel, sex-dependent circuit mechanism and identifying thalamic inhibition as a promising therapeutic target. Future work will entail evaluating local interneuron function, integration of thalamocortical output to the sensory cortex, and restoring behavioral deficits in-vivo. By shifting the focus from cortex-centric models to thalamocortical circuit dynamics, this work will establish a new framework for understanding sensory dysfunction in neurodevelopmental disorders. More broadly, it will reveal how early modulation of subcortical inhibitory circuits can recalibrate developing brain networks, paving the way for circuit-specific therapeutic strategies for ASDs.