
@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 {1017,
	title = {Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS.},
	journal = {Hum Mol Genet},
	volume = {24},
	year = {2015},
	month = {2015 Nov 1},
	pages = {5977-84},
	abstract = {<p>Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross-mammalian comparison of neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will enable us to directly test whether common cellular dysfunction or behavioural outcomes of a genetic mutation are more conserved across species. Using a new rat model of Fragile X Syndrome, we report that Fmr1 knockout (KO) rats exhibit elevated basal protein synthesis and an increase in mGluR-dependent long-term depression in CA1 of the hippocampus that is independent of new protein synthesis. These defects in plasticity are accompanied by an increase in dendritic spine density selectively in apical dendrites and subtle changes in dendritic spine morphology of CA1 pyramidal neurons. Behaviourally, Fmr1 KO rats show deficits in hippocampal-dependent, but not hippocampal-independent, forms of associative recognition memory indicating that the loss of fragile X mental retardation protein (FMRP) causes defects in episodic-like memory. In contrast to previous reports from mice, Fmr1 KO rats show no deficits in spatial reference memory reversal learning. One-trial spatial learning in a delayed matching to place water maze task was also not affected by the loss of FMRP in rats. This is the first evidence for conservation across mammalian species of cellular and physiological hippocampal phenotypes associated with the loss of FMRP. Furthermore, while key cellular phenotypes are conserved they manifest in distinct behavioural dysfunction. Finally, our data reveal novel information about the selective role of FMRP in hippocampus-dependent associative memory.</p>
},
	issn = {1460-2083},
	doi = {10.1093/hmg/ddv299},
	author = {Till, Sally M and Asiminas, Antonis and Jackson, Adam D and Katsanevaki, Danai and Barnes, Stephanie A and Osterweil, Emily K and Bear, Mark F and Chattarji, Sumantra and Wood, Emma R and Wyllie, David J A and Kind, Peter C}
}
