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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Computer Simulation
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism*
  • Glutamic Acid / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Neurons / metabolism*
  • Patch-Clamp Techniques
  • Phenotype
  • Somatosensory Cortex / cytology
  • Somatosensory Cortex / metabolism*
  • Synapses / metabolism*

Substances

  • Fmr1 protein, mouse
  • Fragile X Mental Retardation Protein
  • Glutamic Acid