Glial cells over-prune synapses in Fragile X syndrome model mice

Fragile X syndrome, the most common inherited cause of intellectual disability and autism, arises from the loss of FMRP, an RNA-binding protein that regulates translation. A new study in Scientific Reports reports that in Fmr1 knockout mice, a model of the condition, synapses are smaller than normal and the eye-specific wiring of the retinogeniculate pathway segregates faster than usual, pointing to a disruption in the normal timing of synaptic refinement.

To find out which cell types drive this change, the researchers applied a multi-omic framework to the model mice at postnatal day 7, a critical window for synaptic remodeling in the retinogeniculate pathway, an established system for studying synaptic pruning. Single-cell transcriptomics revealed coordinated alterations in microglia, astrocytes, and neurons in genes linked to synaptic pruning. Computational modeling further showed enhanced astrocyte-to-microglia signaling, particularly through Ephrin A (EphA)- and semaphorin-mediated pathways.

Preliminary lipidomic profiling added a biochemical dimension: the team observed reductions in EphA-associated lipid species that are required for lipid raft stability and receptor localization. Consistent with the transcriptomic profile, a glial engulfment assay indicated that microglia and astroglia in the Fragile X model over-engulf synaptic material in the lateral geniculate nucleus.

Together, these findings identify impaired glial-driven synaptic refinement as an early feature of Fragile X syndrome pathogenesis in this mouse model, and highlight the genes involved in the process as candidate targets for future investigation. The authors note that FMRP is highly expressed in glial cells, yet its role in neural circuit development there had remained poorly defined, making these results a step toward clarifying that role.

Subject of Research: Glial-mediated synaptic pruning in a Fragile X syndrome mouse model

Article Title: Disrupted glial-mediated synaptic refinement in Fragile X syndrome

Article References: Starr, L., Lee, M., Vo, A., Weisenhaus, M., Cheadle, L., Yadav, A., Paryani, F., Shirasu-Hiza, M., Menon, V., & Mason, C. (2026). Disrupted glial-mediated synaptic refinement in Fragile X syndrome. Scientific Reports. https://doi.org/10.1038/s41598-026-75819-z

Image Credits: AI Generated

DOI: 10.1038/s41598-026-75819-z

Keywords: Fragile X syndrome, FMRP, synaptic pruning, microglia, astrocytes, retinogeniculate pathway, single-cell transcriptomics, lipidomics, Ephrin A signaling, Fmr1 knockout mice, neurodevelopment, Disrupted