Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, results from the loss of the RNA-binding protein fragile X mental retardation protein (FMRP). FMRP is a translational regulator and is highly expressed in glial cells, where its role in neural circuit development remains poorly defined. Here, it was observed that Fmr1 knockout mice exhibit reduced synapse size and accelerated eye-specific segregation.
To examine which cell-types participate in this process, a multi-omic framework was applied to FXS model mice at postnatal day 7, a critical window for synaptic remodeling in the retinogeniculate pathway, an established model system utilized to study synaptic pruning. Single-cell transcriptomics revealed coordinated alterations in microglia, astrocytes, and neurons in genes linked to synaptic pruning. Computational modeling further demonstrated enhanced astrocyte-to-microglia signaling, particularly through Ephrin A (EphA)- and semaphorin-mediated pathways, while preliminary lipidomic profiling revealed reductions in EphA-associated lipid species required for lipid raft stability and receptor localization.
Consistent with these observations, a glial engulfment assay indicated that FXS microglia and astroglia over-engulf synaptic material in the lateral geniculate nucleus, supporting the transcriptomic profile. Together, these findings identify impaired glial-driven synaptic refinement as an early feature of FXS pathogenesis, highlighting the genes involved in this process as candidate targets for future investigation. We thank all members of the Mason, Shirasu-Hiza, and Menon labs and the lab of Michael Greenberg (Harvard) for support, discussions, and feedback.
For this research came from the NIH T32GM141882 (LS); T32EY013933 (ML), R35GM127049 (MSH); R01EYR01EY012736 (CAM); R21NS122366 (MSH, CAM); K99MH120051 (LC), and from the Simons Foundation Autism Research Initiative (SFARI) Explorer Award (CM, MSH, ML) and an Antonio Champalimaud Vision Award (CM). Lindsey Starr and Melissa Lee contributed equally to this work. Mimi Shirasu-Hiza, Vilas Menon and Carol Mason are co-senior authors.
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA Departments of Pathology & Cell Biology, Neuroscience and Ophthalmology, Zuckerman Mind Brain Behavior Institute, Columbia University Irving Medical Center, Columbia University, New York, NY, USA Melissa Lee, Amy Vo, Maia Weisenhaus & Carol Mason Department of Neurobiology, Harvard Medical School, MA, Boston, United States Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Irving Medical Center, New York, NY, USA Lindsey Starr, Archana Yadav, Fahad Paryani & Vilas Menon Correspondence to Lindsey Starr or Carol Mason. The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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