The binding of GABA (γ-aminobutyric acid) to extrasynaptic GABAA receptors generates tonic inhibition that acts as a powerful modulator of cortical network activity. Despite GABA being present throughout the extracellular space of the brain, previous work has shown that GABA may differentially modulate the excitability of neuron subtypes according to variation in chloride gradient. Here, using biophysically detailed neuron models, we predict that tonic inhibition can differentially modulate the excitability of neuron subtypes according to variation in electrophysiological properties. Surprisingly, tonic inhibition increased the responsiveness (or gain) in models with features typical for somatostatin interneurons but decreased gain in models with features typical for parvalbumin interneurons. Patch-clamp recordings from cortical interneurons supported these predictions, and further in silico analysis was then performed to seek a putative mechanism underlying gain modulation. We found that gain modulation in models was dependent upon the magnitude of tonic current generated at depolarized membrane potential-a property associated with outward rectifying GABAA receptors. Furthermore, tonic inhibition produced two biophysical changes in models of relevance to neuronal excitability: 1) enhanced action potential repolarization via increased current flow into the dendritic compartment, and 2) reduced activation of voltage-dependent potassium channels. Finally, we show theoretically that reduced potassium channel activation selectively increases gain in models possessing action potential dynamics typical for somatostatin interneurons. Potassium channels in parvalbumin-type models deactivate rapidly and are unavailable for further modulation. These findings show that GABA can differentially modulate interneuron excitability and suggest a mechanism through which this occurs in silico via differences of intrinsic electrophysiological properties.

中文翻译：

---

GABA介导的强直抑制作用可不同地调节皮质中神经元功能亚型的增益。

GABA（γ-氨基丁酸）与突触外GABAA受体的结合产生了强直抑制作用，可作为皮质网络活性的强大调节剂。尽管GABA存在于大脑的整个细胞外空间，但先前的研究表明GABA可能根据氯化物梯度的变化来差异性调节神经元亚型的兴奋性。在这里，使用生物物理上详细的神经元模型，我们预测进补抑制可以根据电生理特性的变化来差异性调节神经元亚型的兴奋性。令人惊讶的是，在具有生长抑素中间神经元典型特征的模型中，进补抑制作用增加了响应性（或增益），但是在具有小白蛋白中间神经元典型特征的模型中，抑制了增益。来自皮层神经元的膜片钳记录支持了这些预测，然后进行了进一步的计算机分析，以寻找潜在的增益调制机制。我们发现模型中的增益调制取决于在去极化膜电位下产生的强音电流的大小，这是与向外整流GABAA受体相关的特性。此外，进补抑制作用在与神经元兴奋性相关的模型中产生了两个生物物理变化：1）通过增加流入树突区的电流，增强了动作电位的复极化作用，以及2）降低了电压依赖性钾通道的激活。最后，我们从理论上证明，在具有生长抑素中间神经元典型动作电位动力学模型中，减少的钾离子通道激活选择性地增加了增益。小白蛋白型模型中的钾通道迅速失活，无法进一步调节。这些发现表明，GABA可以差异地调节神经元间的兴奋性，并通过内部电生理特性的差异提出了一种在计算机中发生这种现象的机制。