Altered dendritic spine function and integration in a mouse model of fragile X syndrome.
|Title||Altered dendritic spine function and integration in a mouse model of fragile X syndrome.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Booker SA, Domanski APF, Dando OR, Jackson AD, Isaac JTR, Hardingham GE, Wyllie DJA, Kind PC|
|Date Published||2019 Oct 23|
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.
|Alternate Journal||Nat Commun|
|PubMed Central ID||PMC6811549|
|Grant List||MR/P006213/1 / / RCUK | Medical Research Council (MRC) /|