Recent experimental literature has revealed that GABAergic interneurons exhibit increased activity prior to seizure onset, alongside additional evidence that such activity is synchronous and may arise abruptly. These findings have led some to hypothesize that this interneuronal activity may serve a causal role in driving the sudden change in brain activity that heralds seizure onset. However, the mechanisms predisposing an inhibitory network toward increased activity, specifically prior to ictogenesis, without a permanent change to inputs to the system remain unknown. We address this question by comparing simulated inhibitory networks containing control interneurons and networks containing hyperexcitable interneurons modeled to mimic treatment with 4-Aminopyridine (4-AP), an agent commonly used to model seizures in vivo and in vitro. Our in silico study demonstrates that model inhibitory networks with 4-AP interneurons are more prone than their control counterparts to exist in a bistable state in which asynchronously firing networks can abruptly transition into synchrony driven by a brief perturbation. This transition into synchrony brings about a corresponding increase in overall firing rate. We further show that perturbations driving this transition could arise in vivo from background excitatory synaptic activity in the cortex. Thus, we propose that bistability explains the increase in interneuron activity observed experimentally prior to seizure via a transition from incoherent to coherent dynamics. Moreover, bistability explains why inhibitory networks containing hyperexcitable interneurons are more vulnerable to this change in dynamics, and how such networks can undergo a transition without a permanent change in the drive. We note that while our comparisons are between networks of control and ictogenic neurons, the conclusions drawn specifically relate to the unusual dynamics that arise prior to seizure, and not seizure onset itself. However, providing a mechanistic explanation for this phenomenon specifically in a pro-ictogenic setting generates experimentally testable hypotheses regarding the role of inhibitory neurons in pre-ictal neural dynamics, and motivates further computational research into mechanisms underlying a newly hypothesized multi-step pathway to seizure initiated by inhibition.

中文翻译：

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抑制性网络双稳态解释了癫痫发作前增加的神经元间活动。

最近的实验文献表明，GABA 能中间神经元在癫痫发作前表现出增加的活动，同时还有其他证据表明此类活动是同步的并且可能突然出现。这些发现导致一些人假设这种神经元间活动可能在驱动预示癫痫发作的大脑活动的突然变化中起因果作用。然而，使抑制网络倾向于增加活动的机制，特别是在 ictogenesis 之前，没有永久改变系统输入的机制仍然未知。我们通过比较包含控制中间神经元的模拟抑制网络和包含过度兴奋中间神经元的网络来解决这个问题，该网络被建模以模拟 4-氨基吡啶 (4-AP) 的治疗，4-氨基吡啶 (4-AP) 是一种常用于模拟体内和体外癫痫发作的药剂。我们的计算机研究表明，具有 4-AP 中间神经元的模型抑制网络比它们的控制对应物更容易处于双稳态，在这种状态下，异步发射网络可以突然转变为由短暂扰动驱动的同步。这种向同步的转变带来了整体发射率的相应增加。我们进一步表明，驱动这种转变的扰动可能在体内由皮层中的背景兴奋性突触活动引起。因此，我们提出双稳态解释了在癫痫发作之前通过从不连贯到连贯动力学的转变在实验中观察到的中间神经元活动的增加。此外，双稳态解释了为什么包含过度兴奋中间神经元的抑制网络更容易受到这种动态变化的影响，以及此类网络如何在不改变驱动器的情况下进行过渡。我们注意到，虽然我们的比较是在控制网络和 ictogenic 神经元之间进行的，但得出的结论特别涉及癫痫发作之前出现的异常动态，而不是癫痫发作本身。然而，特别是在 pro-ictogenic 环境中为这种现象提供机械解释会产生关于抑制性神经元在发作前神经动力学中的作用的实验上可测试的假设，并激发对新假设的多步骤癫痫发作途径背后的机制的进一步计算研究由抑制引发。得出的结论特别涉及癫痫发作之前出现的异常动态，而不是癫痫发作本身。然而，特别是在 pro-ictogenic 环境中为这种现象提供机械解释会产生关于抑制性神经元在发作前神经动力学中的作用的实验上可测试的假设，并激发对新假设的多步骤癫痫发作途径背后的机制的进一步计算研究由抑制引发。得出的结论特别涉及癫痫发作之前出现的异常动态，而不是癫痫发作本身。然而，特别是在 pro-ictogenic 环境中为这种现象提供机械解释会产生关于抑制性神经元在发作前神经动力学中的作用的实验上可测试的假设，并激发对新假设的多步骤癫痫发作途径背后的机制的进一步计算研究由抑制引发。