Altered dendritic spine function and integration in a mouse model of fragile X syndrome

Sam A. Booker, Aleksander P. F. Domanski, Owen R. Dando, Adam D. Jackson, John T. R. Isaac, Giles E. Hardingham, David J. A. Wyllie*, Peter C. Kind

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

35 Citations (Scopus)
92 Downloads (Pure)


Cellular and circuit hyperexcitability are core features of fragile X syndrome and related autism spectrum disorder models. However, the cellular and synaptic bases of this hyperexcitability have proved elusive. We report in a mouse model of fragile X syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, fewer spines are required to trigger an action potential with near-simultaneous uncaging at multiple spines. This is, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents, and increased NMDA receptor signaling. Using super-resolution microscopy we detect no change in dendritic spine morphology, indicating no structure-function relationship at this age. However, ultrastructural analysis shows a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine glutamate currents. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability.

Original languageEnglish
Article number4813 (2019)
Number of pages14
JournalNature Communications
Publication statusPublished - 23 Oct 2019


  • development of the nervous system
  • diseases of the nervous system
  • neuronal physiology
  • somatosensory system
  • spine regulation and structure


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