Neuron
Volume 101, Issue 4, 20 February 2019, Pages 648-661.e4
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Article
Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models

https://doi.org/10.1016/j.neuron.2018.12.026Get rights and content
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Highlights

  • Four mouse models of autism share a common increase in E-I ratio in sensory cortex

  • E-I ratio changes acted to stabilize synaptic depolarization and spiking

  • Sensory-evoked firing rate in vivo was remarkably normal and sometimes decreased

  • These findings suggest E-I ratio changes are compensatory in autism

Summary

Distinct genetic forms of autism are hypothesized to share a common increase in excitation-inhibition (E-I) ratio in cerebral cortex, causing hyperexcitability and excess spiking. We provide a systematic test of this hypothesis across 4 mouse models (Fmr1−/y, Cntnap2−/−, 16p11.2del/+, Tsc2+/−), focusing on somatosensory cortex. All autism mutants showed reduced feedforward inhibition in layer 2/3 coupled with more modest, variable reduction in feedforward excitation, driving a common increase in E-I conductance ratio. Despite this, feedforward spiking, synaptic depolarization, and spontaneous spiking were largely normal. Modeling revealed that E and I conductance changes in each mutant were quantitatively matched to yield stable, not increased, synaptic depolarization for cells near spike threshold. Correspondingly, whisker-evoked spiking was not increased in vivo despite detectably reduced inhibition. Thus, elevated E-I ratio is a common circuit phenotype but appears to reflect homeostatic stabilization of synaptic drive rather than driving network hyperexcitability in autism.

Keywords

E-I ratio
cerebral cortex
somatosensory cortex
circuit excitability
Fragile X
homeostasis
autism
excitation
inhibition

Cited by (0)

2

Present address: Max Delbrück Center for Molecular Medicine, Berlin, Germany

3

These authors contributed equally

4

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