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bioRxiv · 10.64898/2026.08.28.747531

Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome

Ye, J.·Surl, J. A. B.·McKechanie, A. G.·Dando, O.·Straathof, M.·Dijkhuizen, R. M.·Stanfield, A. C.·Till, S. M.·Kind, P. C.
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Abstract

Fragile X syndrome (FXS), a leading monogenic cause of intellectual disability and autism-related features, results from loss of fragile X messenger ribonucleoprotein (FMRP). Although early synaptic and cellular abnormalities associated with the loss of FMRP are well described, it remains unclear how these changes shape the maturation of large-scale functional networks, or whether early pharmacological intervention can normalize circuit development. Our previous work demonstrated that cognitive deficits in Fmr1-/y rats emerge during development and can be prevented by brief early-life lovastatin treatment. Here, we asked whether large-scale functional connectivity (FC) shows a similarly dynamic developmental trajectory and whether early intervention alters its emergence. Using longitudinal resting-state functional magnetic resonance imaging (rsfMRI), we found that Fmr1-/y rats displayed an age-dependent FC phenotype, with increased connectivity within the retrosplenial cortex (RSC) at 4 weeks but reduced connectivity within the RSC and distributed brain networks by adulthood compared with wild-type controls. This suggests FC abnormalities emerge over development rather than representing a stable deficit. In contrast to its effects on cognitive measures, brief early-life lovastatin treatment rescues did not prevent the emergence of connectivity abnormalities. Reduced RSC FC was also observed in a small cohort of individuals with FXS (n = 5 per group), supporting further investigation of functional connectivity measures alongside behavioural and molecular endpoints in translational studies of FXS.

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Ye, J., Surl, J. A. B., McKechanie, A. G., Dando, O., Straathof, M., Dijkhuizen, R. M., Stanfield, A. C., Till, S. M., Kind, P. C.. 2026-09-03. Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome. https://doi.org/10.64898/2026.08.28.747531

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