TY - JOUR
T1 - Altered dendritic spine function and integration in a mouse model of fragile X syndrome
AU - Booker, Sam A.
AU - Domanski, Aleksander P. F.
AU - Dando, Owen R.
AU - Jackson, Adam D.
AU - Isaac, John T. R.
AU - Hardingham, Giles E.
AU - Wyllie, David J. A.
AU - Kind, Peter C.
PY - 2019/10/23
Y1 - 2019/10/23
N2 - 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.
AB - 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.
KW - development of the nervous system
KW - diseases of the nervous system
KW - neuronal physiology
KW - somatosensory system
KW - spine regulation and structure
UR - http://www.scopus.com/inward/record.url?scp=85074096947&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-11891-6
DO - 10.1038/s41467-019-11891-6
M3 - Article (Academic Journal)
C2 - 31645626
AN - SCOPUS:85074096947
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
M1 - 4813 (2019)
ER -