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Nat Commun. 2019 Oct 23;10(1):4814. doi: 10.1038/s41467-019-12736-y.

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

Domanski APF1,2,3,4, Booker SA5,6,7, Wyllie DJA5,6,7,8, Isaac JTR9,10, Kind PC11,12,13,14.

Author information

1
School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK. aleks.domanski@bristol.ac.uk.
2
Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. aleks.domanski@bristol.ac.uk.
3
Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. aleks.domanski@bristol.ac.uk.
4
Developmental Synaptic Plasticity Section, NINDS, NIH, Bethesda, MD, 20892, USA. aleks.domanski@bristol.ac.uk.
5
Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
6
Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
7
Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
8
Centre for Brain Development and Repair, NCBS, GKVK Campus, Bangalore, 560065, India.
9
Developmental Synaptic Plasticity Section, NINDS, NIH, Bethesda, MD, 20892, USA. jisaac5@ITS.JNJ.com.
10
Janssen Neuroscience, J&J London Innovation Centre, J&J London Innovation Centre, One Chapel Place, London, W1G 0B, UK. jisaac5@ITS.JNJ.com.
11
Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. pkind@ed.ac.uk.
12
Patrick Wild Centre, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. pkind@ed.ac.uk.
13
Simons Initiative for the Developing Brain, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK. pkind@ed.ac.uk.
14
Centre for Brain Development and Repair, NCBS, GKVK Campus, Bangalore, 560065, India. pkind@ed.ac.uk.

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.

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