MECHANISMS UNDERLYING THE PATHOPHYSIOLOGY OF FRAGILE X SYNDROME

We discovered the role of MMP9 in pathophysiology of FXS and demonstrated beneficial effects of minocycline on synapse development and behavioral performance in an animal model of FXS (Bilousova et al., 2009; Rotschafer et al., 2012; Dansie et al., 2013; Sidhu et al., 2014). These findings prompted several clinical trials that tested the effects of minocycline treatment in individuals with FXS (Paribello et al., 2010; Utari et al., 2010; Leigh et al., 2013). Ongoing studies focus on the role of MMP9 and extracellular matrix in autistic behaviors associated with FXS, including the mechanisms of auditory hypersensitivity (Lovelace et al., 2016; Wen et al., 2018; Pirbhoy et al., 2020). Most recent work uncovered key developmental defects in parvalbumin (PV) interneurons and the role of extracellular matrix in regulating cortical connectivity in Fragile X mouse models. We continue to explore the role of astrocytes in the development of inhibitory circuits and shaping normal inhibitory responses in mouse brain with potential for examining the mechanisms in patient-derived human astrocytes and translating the results into successful clinical trials.