Division of Clinical and Computational Neuroscience, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
Departments of Medicine (Neurology) and Physiology, University of Toronto, Toronto, ON, Canada.
Front Neural Circuits. 2020 Jan 14;13:81. doi: 10.3389/fncir.2019.00081. eCollection 2019.
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 and . Our 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 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.
最近的实验文献表明，在癫痫发作前，GABA 能中间神经元的活动增加，此外还有证据表明这种活动是同步的，可能突然出现。这些发现促使一些人假设这种中间神经元活动可能在驱动预示癫痫发作开始的大脑活动的突然变化中起因果作用。然而，导致抑制性网络活动增加的机制，特别是在癫痫发作发生之前，而系统的输入没有永久性改变，仍然未知。我们通过比较包含对照中间神经元的模拟抑制性网络和包含模拟用 4-氨基吡啶（4-AP）治疗的兴奋性过高中间神经元的网络来解决这个问题，4-AP 是一种常用于模拟癫痫发作的药物。我们的研究表明，含有 4-AP 中间神经元的模型抑制性网络比其对照物更容易处于双稳态状态，在这种状态下，异步发射的网络可以在短暂的扰动下突然过渡到同步。这种同步过渡导致整体发射率相应增加。我们进一步表明，驱动这种过渡的扰动可能来自皮质中的背景兴奋性突触活动。因此，我们提出双稳态通过从非相干到相干动力学的转变来解释实验中观察到的癫痫发作前中间神经元活动的增加。此外，双稳态解释了为什么含有兴奋性过高中间神经元的抑制性网络更容易受到这种动力学变化的影响，以及这些网络如何在没有驱动永久性变化的情况下发生转变。我们注意到，虽然我们的比较是在对照和致痫神经元的网络之间进行的，但得出的结论具体涉及到癫痫发作前出现的异常动力学，而不是癫痫发作本身。然而，在致痫环境中对这种现象提供一种机制解释，会产生关于抑制性神经元在癫痫发作前神经动力学中作用的可实验检验假说，并促使对由抑制引发的新假设的多步骤癫痫发作途径的潜在机制进行进一步的计算研究。
