1. Altered dendritic spine function and integration in a mouse model of fragile X syndrome.
- Author
-
Booker SA, Domanski APF, Dando OR, Jackson AD, Isaac JTR, Hardingham GE, Wyllie DJA, and Kind PC
- Subjects
- Animals, Dendritic Spines ultrastructure, Disease Models, Animal, Fragile X Mental Retardation Protein genetics, Fragile X Syndrome genetics, Fragile X Syndrome pathology, Male, Mice, Mice, Knockout, Neurogenesis, Neurons metabolism, Neurons ultrastructure, Patch-Clamp Techniques, Somatosensory Cortex cytology, Synapses ultrastructure, Action Potentials physiology, Dendritic Spines metabolism, Fragile X Syndrome metabolism, Glutamic Acid metabolism, Synapses metabolism
- Abstract
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.
- Published
- 2019
- Full Text
- View/download PDF