Booker, Sam

Kind, Peter

Sibley, Chris

Abbott, Cathy

Sumera, Anna

2026-05-05T15:54:30Z

2026-05-05

Fragile X Syndrome (FXS) is a common single-gene cause of autism and intellectual disability. Prevalent symptoms such as seizures and sensory hypersensitivity arise from cortical dysfunction, which could be underpinned by cortical hyperexcitability. Despite extensive research, currently there are no effective therapies targeting the underlying mechanisms, which could be due to species differences and limited understanding of how cortical dysfunction arises during development. In this thesis, I examined the first 4 weeks of postnatal development of the somatosensory cortex (S1) in a rat model of FXS, by characterizing the electrophysiological properties and morphology of S1 neurons, combined with an investigation of interneuron density. Using whole-cell patch clamp recordings from layer 4 of S1, I found that Fmr1-/y stellate cells (SCs) are hyperexcitable during early development, in agreement with previous research. Thanks to the high temporal resolution of these recordings, I have identified multiple phases of development in Fmr1-/y SCs, with distinct periods of intrinsic hyperexcitability flanked by typical excitability, which were not previously described. The different phases could arise due to different mechanisms, as SCs have a reduced dendritic complexity during the second postnatal week that is normalized before hyperexcitability arises for the second time. Changes in excitability are accompanied by an increase in the density of somatostatin-expressing interneurons. Early pharmacological treatment with BPN14770 was able to normalize the action potential output and morphology of the SCs during the second postnatal week, but did not provide a long-term rescue of excitability. Additionally, I have identified cell type-specific transcriptomic differences in the developing somatosensory cortex of Fmr1-/y rats, which support the physiological changes. Together, these data suggest that the developmental trajectory taken by the Fmr1-/y cortex is significantly altered, but partially amenable to therapeutic intervention albeit without long-term effects.

https://era.ed.ac.uk/handle/1842/44673

https://doi.org/10.7488/era/7188

en

Fragile X Syndrome

FXS

Somatosensory Cortex

Hyperexcitability

development stages of the cortex

Interneurons

Postnatal development of the somatosensory cortex in a rat model of Fragile X Syndrome

Thesis

Doctoral

PhD Doctor of Philosophy