Cellular and synaptic phenotypes lead to disrupted information processing in Fmr1-KO mouse layer 4 barrel cortex

Aleksander P. F. Domanski (), Sam A. Booker, David J. A. Wyllie, John T. R. Isaac () and Peter C. Kind ()
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Aleksander P. F. Domanski: University of Bristol
Sam A. Booker: University of Edinburgh
David J. A. Wyllie: University of Edinburgh
John T. R. Isaac: Developmental Synaptic Plasticity Section, NINDS, NIH
Peter C. Kind: University of Edinburgh

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12736-y

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