Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome
- 1University of Edinburgh
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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BibTeX
@misc{ye2026loss,
title = {{Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome}},
author = {J. Ye and J. A. B. Surl and A. G. McKechanie and O. Dando and M. Straathof and R. M. Dijkhuizen and A. C. Stanfield and S. M. Till and P. C. Kind},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.747531},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.747531v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Loss of FMRP leads to translationally relevant functional connectivity differences in a rat model of Fragile X Syndrome
AU - J. Ye
AU - J. A. B. Surl
AU - A. G. McKechanie
AU - O. Dando
AU - M. Straathof
AU - R. M. Dijkhuizen
AU - A. C. Stanfield
AU - S. M. Till
AU - P. C. Kind
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.747531
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.747531v1
AB - 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.
ER -