A Agmon

A Cardona

A Contractor

A Crocker-Buque

A Losonczy

BE Pfeiffer

BJ Wainger

BM Dolan

C Henderson

CC Petersen

CH Choi

D Schubert

DH Brager

DJ Kelley

E Berry-Kravis

E Berry‐Kravis

EG Harlow

EL White

GordonX Wang

H Jia

I Bureau

I Nikonenko

J Clements

J Schindelin

JC Darnell

JC Magee

JR Gibson

JT Gonçalves

K Fox

KM Harris

L Miller

LM Palmer

LS Wijetunge

M Lavzin

M Maravall

MC Ashby

MF Bear

MF Nolan

N Toni

P-Y Deng

SA Irwin

T Branco

TA Comery

W Rall

Y Zhang

Crossref

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

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.</p

Booker, Sam A.

Domanski, Aleksander P. F.

Dando, Owen R.

Jackson, Adam D.

Isaac, John T. R.

Hardingham, Giles E.

Wyllie, David J. A.

Kind, Peter C.

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https://research-information.bris.ac.uk/ws/files/218501959/s41467_019_11891_6.pdf

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

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