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Nat Commun. 2019 Oct 23;10(1):4813. doi: 10.1038/s41467-019-11891-6.

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

Booker SA1,2,3,4, Domanski APF1,5, Dando OR1,2,3,4,6, Jackson AD1,2,3,4, Isaac JTR7,8, Hardingham GE1,2,3,4,6, Wyllie DJA9,10,11,12, Kind PC13,14,15,16.

Author information

1
Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
2
Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
3
Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
4
Centre for Brain Development and Repair, NCBS, GKVK Campus, Bangalore, 560065, India.
5
School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK.
6
UK Dementia Research Institute, University of Edinburgh, Chancellor's Buildings, Little France, Edinburgh, EH16 4SB, UK.
7
Developmental Synaptic Plasticity Section, NINDS, NIH, Bethesda, MD, 20892, USA.
8
Janssen Neuroscience, J&J London Innovation Centre, One Chapel Place, London, W1G 0B, UK.
9
Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. david.j.a.wyllie@ed.ac.uk.
10
Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. david.j.a.wyllie@ed.ac.uk.
11
Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. david.j.a.wyllie@ed.ac.uk.
12
Centre for Brain Development and Repair, NCBS, GKVK Campus, Bangalore, 560065, India. david.j.a.wyllie@ed.ac.uk.
13
Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. P.Kind@ed.ac.uk.
14
Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. P.Kind@ed.ac.uk.
15
Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. P.Kind@ed.ac.uk.
16
Centre for Brain Development and Repair, NCBS, GKVK Campus, Bangalore, 560065, India. P.Kind@ed.ac.uk.

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.

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