Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models
Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models
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DOI：
10.1016/j.neuron.2018.12.026
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发表时间：
2019-02-20
期刊：
影响因子：
16.2
通讯作者：
Feldman, Daniel E.
中科院分区：
文献类型：
--
作者：
Antoine, Michelle W.;Langberg, Tomer;Feldman, Daniel E.
不同的自闭症遗传形式被假设为大脑皮层中兴奋抑制（E-I）比例的共同增加，导致过度兴奋和过度尖峰。我们在4种小鼠模型(Fmr1(-/y), Cntnap2(-/-), 16p11.2（del/+), Tsc2(+/-)）中对这一假设进行了系统的检验，重点是体感觉皮层。所有自闭症突变体均表现出2/3层前馈抑制减弱，同时前馈兴奋减弱更为温和，导致E-I电导比普遍增加。尽管如此，前馈尖峰、突触去极化和自发尖峰在很大程度上是正常的。模型显示，每个突变体的E和I电导变化在数量上匹配，在峰值阈值附近的细胞产生稳定的突触去极化，而不是增加。相应地，尽管抑制作用明显减弱，但须诱发的峰值在体内并没有增加。因此，升高的E-I比率是一种常见的电路表型，但似乎反映了自闭症突触驱动的稳态稳定，而不是驱动网络的过度兴奋性。
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(-/-), 16p11.2(del/+), 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.