Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Krembil Research Institute, Division of Fundamental Neurobiology, Toronto Western Hospital, Toronto, Ontario M5T 0S8, Canada.
Krembil Research Institute, Division of Fundamental Neurobiology, Toronto Western Hospital, Toronto, Ontario M5T 0S8, Canada; National Optics Institute, Biophotonics, Quebec, Canada G1P 4S4.
Neurobiol Dis. 2020 Dec;146:105124. doi: 10.1016/j.nbd.2020.105124. Epub 2020 Sep 30.
The transition between seizure and non-seizure states in neocortical epileptic networks is governed by distinct underlying dynamical processes. Based on the gamma distribution of seizure and inter-seizure durations, over time, seizures are highly likely to self-terminate; whereas, inter-seizure durations have a low chance of transitioning back into a seizure state. Yet, the chance of a state transition could be formed by multiple overlapping, unknown synaptic mechanisms. To identify the relationship between the underlying synaptic mechanisms and the chance of seizure-state transitions, we analyzed the skewed histograms of seizure durations in human intracranial EEG and seizure-like events (SLEs) in local field potential activity from mouse neocortical slices, using an objective method for seizure state classification. While seizures and SLE durations were demonstrated to have a unimodal distribution (gamma distribution shape parameter >1), suggesting a high likelihood of terminating, inter-SLE intervals were shown to have an asymptotic exponential distribution (gamma distribution shape parameter <1), suggesting lower probability of cessation. Then, to test cellular mechanisms for these distributions, we studied the modulation of synaptic neurotransmission during, and between, the in vitro SLEs. Using simultaneous local field potential and whole-cell voltage clamp recordings, we found a suppression of presynaptic glutamate release at SLE termination, as demonstrated by electrically- and optogenetically-evoked excitatory postsynaptic currents (EPSCs), and focal hypertonic sucrose application. Adenosine A1 receptor blockade interfered with the suppression of this release, changing the inter-SLE shape parameter from asymptotic exponential to unimodal, altering the chance of state transition occurrence with time. These findings reveal a critical role for presynaptic glutamate release in determining the chance of neocortical seizure state transitions.
新皮层癫痫网络中发作和非发作状态之间的转变受不同的潜在动力学过程控制。基于发作和发作间持续时间的伽马分布，随着时间的推移，发作极有可能自行终止；而发作间持续时间再次进入发作状态的可能性很小。然而，状态转变的可能性可能是由多个重叠的、未知的突触机制形成的。为了确定潜在突触机制与发作状态转变机会之间的关系，我们使用客观的发作状态分类方法，分析了人类颅内 EEG 中的发作持续时间和局部场电位活动中的发作样事件（SLE）的偏态直方图，对小鼠新皮层切片。虽然发作和 SLE 持续时间表现出单峰分布（伽马分布形状参数>1），表明终止的可能性很高，但 SLE 之间的间隔表现出渐近指数分布（伽马分布形状参数<1），表明终止的可能性较低。然后，为了测试这些分布的细胞机制，我们研究了体外 SLE 期间和之间突触神经传递的调制。通过同时进行局部场电位和全细胞膜片钳记录，我们发现 SLE 终止时，突触前谷氨酸释放受到抑制，如电和光遗传学诱发的兴奋性突触后电流（EPSC）和焦点高渗蔗糖应用所示。腺苷 A1 受体阻断干扰了这种释放的抑制，将 SLE 之间的形状参数从渐近指数变为单峰，随着时间的推移改变状态转变发生的机会。这些发现揭示了突触前谷氨酸释放在决定新皮层发作状态转变机会中的关键作用。
