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Neuron. 2019 Jan 21. pii: S0896-6273(18)31126-7. doi: 10.1016/j.neuron.2018.12.026. [Epub ahead of print]

Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models.

Author information

1
Department of Molecular and Cellular Biology and Helen Wills Neuroscience Institute, UC Berkeley, Berkeley, CA 94720, USA. Electronic address: mwantoine@berkeley.edu.
2
Department of Molecular and Cellular Biology and Helen Wills Neuroscience Institute, UC Berkeley, Berkeley, CA 94720, USA.
3
Department of Molecular and Cellular Biology and Helen Wills Neuroscience Institute, UC Berkeley, Berkeley, CA 94720, USA. Electronic address: dfeldman@berkeley.edu.

Abstract

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; Fragile X; autism; cerebral cortex; circuit excitability; excitation; homeostasis; inhibition; somatosensory cortex

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