TY - JOUR
T1 - Cellular and synaptic phenotypes lead to disrupted information processing in Fmr1-KO mouse layer 4 barrel cortex
AU - Domanski, Aleksander P. F.
AU - Booker, Sam A.
AU - Wyllie, David J. A.
AU - Isaac, John T. R.
AU - Kind, Peter C.
PY - 2019/10/23
Y1 - 2019/10/23
N2 - 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.
AB - 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.
KW - cellular neuroscience
KW - computational neuroscience
KW - diseases of the nervous system
KW - neuronal physiology
KW - somatosensory system
UR - http://www.scopus.com/inward/record.url?scp=85074114719&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12736-y
DO - 10.1038/s41467-019-12736-y
M3 - Article (Academic Journal)
C2 - 31645553
AN - SCOPUS:85074114719
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
M1 - 4814 (2019)
ER -