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Disrupted glial-mediated synaptic refinement and lipid signaling in Fragile X syndrome

Poster Session A - Saturday, March 7, 2026, 3:00 – 5:00 pm PST, Fairview/Kitsilano Ballrooms

Lindsey Starr¹ (ls4007@cumc.columbia.edu), Melissa Lee, Mimi Shirasu-Hiza, Carol Mason, Vilas Menon; ¹Columbia University Vagelos College of Physicians and Surgeons

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism, resulting from mutations in the FMR1 gene that encodes fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein that is known to regulate transcription in neurons; thus, studies of FMRP in FXS have focused on neurons. However, FMRP is also highly expressed in glial cells, where its role in neural development is poorly defined. To address this gap, a multi-omic approach was applied to Fmr1 knockout (KO) mice at postnatal day 7, a critical period for synaptic refinement. Single nucleus RNA sequencing of wildtype and Fmr1 KO mice revealed transcriptional changes in astrocytes, microglia, and neurons in genes that regulate phagocytosis and synaptic pruning. Consistent with these findings, Fmr1 KO mice exhibited reduced retinogeniculate synapse size, accelerated eye-specific segregation, and increased glial engulfment of synaptic material, as assessed by confocal imaging-based quantification of synapse morphology and glial colocalization with synaptic markers. To investigate the mechanisms underlying these abnormalities, computational modeling of ligand-receptor interactions showed increased predicted astrocyte-to-microglia signaling in Fmr1 KO mice via the Ephrin A (EPHA) and semaphorin pathways. Given the dependence of these pathways on membrane lipid composition, lipidomic profiling was performed which showed reduced EPHA-associated lipid species in Fmr1 KO mice that was reversed with Lovastatin. Together, these findings suggest that altered membrane composition contributes to dysregulated pruning-related signaling in FXS and highlight lipid metabolism and glial function as potential therapeutic interventions for FXS during early circuit development.

Topic Area: EXECUTIVE PROCESSES: Development &aging