
@article {67817,
	title = {Altered dendritic spine function and integration in a mouse model of fragile X syndrome.},
	journal = {Nat Commun},
	volume = {10},
	year = {2019},
	month = {2019 Oct 23},
	pages = {4813},
	abstract = {<p>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>
},
	issn = {2041-1723},
	doi = {10.1038/s41467-019-11891-6},
	author = {Booker, Sam A and Domanski, Aleksander P F and Dando, Owen R and Jackson, Adam D and Isaac, John T R and Hardingham, Giles E and Wyllie, David J A and Kind, Peter C}
}
@article {67818,
	title = {Cellular and synaptic phenotypes lead to disrupted information processing in Fmr1-KO mouse layer 4 barrel cortex.},
	journal = {Nat Commun},
	volume = {10},
	year = {2019},
	month = {2019 Oct 23},
	pages = {4814},
	abstract = {<p>Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). How developmental changes in neuronal function culminate in network dysfunction that underlies sensory hypersensitivities is unknown. By systematically studying cellular and synaptic properties of layer 4 neurons combined with cellular and network simulations, we explored how the array of phenotypes in Fmr1-knockout (KO) mice produce circuit pathology during development. We show that many of the cellular and synaptic pathologies in Fmr1-KO mice are antagonistic, mitigating circuit dysfunction, and hence may be compensatory to the primary pathology. Overall, the layer 4 network in the Fmr1-KO exhibits significant alterations in spike output in response to thalamocortical input and distorted sensory encoding. This developmental loss of layer 4 sensory encoding precision would contribute to subsequent developmental alterations in layer 4-to-layer 2/3 connectivity and plasticity observed in Fmr1-KO mice, and circuit dysfunction underlying sensory hypersensitivity.</p>
},
	issn = {2041-1723},
	doi = {10.1038/s41467-019-12736-y},
	author = {Domanski, Aleksander P F and Booker, Sam A and Wyllie, David J A and Isaac, John T R and Kind, Peter C}
}
