@article {95782, title = {Novel insights in plasticity and learning impairments in Fragile X Syndrome.}, journal = {Brain Res Bull}, year = {2021}, month = {2021 Jul 07}, abstract = {

The function of brain circuits relies on high-fidelity information transfer, precisely controlling integration of synaptic input, leading to neuronal output. Synaptic inputs arrive primarily at dendrites, where they undergo integration and summation throughout the somatodendritic domain, ultimately leading to axonal output. Emerging evidence suggests that the ability of neurons to transfer synaptic information and modulate their output is impaired in the neurodevelopmental disorder Fragile X Syndrome. Indeed, how neurons may or may not respond to sensory information during development that leads to compensation of their activity appears to be a salient feature of rodent models of Fragile X Syndrome. In this review we summarise recent findings that have shone light on the ability of neurons in sensory and limbic circuits to reliably code information. We highlight which aspects of this transform are underlain by either direct loss of FMRP in Fragile X Syndrome and which likely result from compensatory or homeostatic alterations to neuron function. Dissection of these mechanisms effect on neuronal plasticity throughout development will have direct implications for individuals with Fragile X Syndrome, directing the timing and duration of different treatment options.

}, issn = {1873-2747}, doi = {10.1016/j.brainresbull.2021.06.025}, author = {Booker, Sam A and Kind, Peter C} } @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 = {

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.

}, 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 = {

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.

}, 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} }