PT  - JOURNAL ARTICLE
AU  - Sam A. Booker
AU  - Aleksander P.F. Domanski
AU  - Owen R. Dando
AU  - Adam D. Jackson
AU  - John T.R. Isaac
AU  - Giles E. Hardingham
AU  - David J.A. Wyllie
AU  - Peter C. Kind
TI  - Altered dendritic spine function and integration in a mouse model of Fragile X Syndrome
AID  - 10.1101/396986
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 396986
4099  - http://biorxiv.org/content/early/2018/08/21/396986.short
4100  - http://biorxiv.org/content/early/2018/08/21/396986.full
AB  - Cellular and circuit hyperexcitability are core features of Fragile X Syndrome and related autism spectrum disorder models. However, a synaptic basis for this hyperexcitability has proved elusive. We show 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, near-simultaneous uncaging at multiple spines revealed fewer spines are required to trigger an action potential. This arose, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents. Super-resolution microscopy revealed no change in dendritic spine morphology, pointing to an absence of a structure-function relationship. However, ultrastructural analysis revealed a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine excitatory currents following glutamate uncaging. 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.