Massachusetts General Hospital, Boston, Massachusetts 02114.
Harvard Medical School, Boston, MA 02115.
J Neurosci. 2019 Jan 16;39(3):557-575. doi: 10.1523/JNEUROSCI.0719-17.2018. Epub 2018 Nov 16.
Epileptic networks are characterized by two outputs: brief interictal spikes and rarer, more prolonged seizures. Although either output state is readily modeled and induced experimentally, the transition mechanisms are unknown, in part because no models exhibit both output states spontaneously. small-world neural networks were built using single-compartment neurons whose physiological parameters were derived from dual whole-cell recordings of pyramidal cells in organotypic hippocampal slice cultures that were generating spontaneous seizure-like activity. , neurons were connected by abundant local synapses and rare long-distance synapses. Activity-dependent synaptic depression and gradual recovery delimited synchronous activity. Full synaptic recovery engendered interictal population spikes that spread via long-distance synapses. When synaptic recovery was incomplete, postsynaptic neurons required coincident activation of multiple presynaptic terminals to reach firing threshold. Only local connections were sufficiently dense to spread activity under these conditions. This coalesced network activity into traveling waves whose velocity varied with synaptic recovery. Seizures were comprised of sustained traveling waves that were similar to those recorded during experimental and human neocortical seizures. Sustained traveling waves occurred only when wave velocity, network dimensions, and the rate of synaptic recovery enabled wave reentry into previously depressed areas at precisely ictogenic levels of synaptic recovery. Wide-field, cellular-resolution GCamP7b calcium imaging demonstrated similar initial patterns of activation in the hippocampus, although the anatomical distribution of traveling waves of synaptic activation was altered by the pattern of synaptic connectivity in the organotypic hippocampal cultures. When computerized distributed neural network models are required to generate both features of epileptic networks (i.e., spontaneous interictal population spikes and seizures), the network structure is substantially constrained. These constraints provide important new hypotheses regarding the nature of epileptic networks and mechanisms of seizure onset.
短暂的发作间棘波和更罕见、更持久的癫痫发作。尽管这两种输出状态都很容易被建模和实验诱导，但过渡机制尚不清楚，部分原因是没有模型自发表现出这两种输出状态。小世界神经网络是使用单室神经元构建的，其生理参数源自器官型海马切片培养物中锥体神经元的双全细胞记录，这些培养物产生自发的癫痫样活动。神经元通过丰富的局部突触和罕见的远距离突触连接。活动依赖性突触抑制和逐渐恢复限定了同步活动。完全的突触恢复会产生通过远距离突触传播的发作间群体尖峰。当突触恢复不完全时，突触后神经元需要多个突触前末梢的同时激活才能达到放电阈值。只有局部连接足够密集，才能在这些条件下传播活动。这种合并的网络活动形成了传播波，其速度随突触恢复而变化。癫痫发作由持续的传播波组成，这些波类似于在实验和人类新皮质癫痫发作中记录到的波。只有当波速、网络尺寸和突触恢复率使波能够以恰好达到致痫性突触恢复水平的方式重新进入先前被抑制的区域时，才会发生持续的传播波。宽场、细胞分辨率的 GCamP7b 钙成像显示了海马体中类似的初始激活模式，尽管在器官型海马培养物中，突触激活的传播波的解剖分布因突触连接模式而改变。当需要计算机化的分布式神经网络模型来产生癫痫网络的两种特征（即自发的发作间群体尖峰和癫痫发作）时，网络结构会受到很大的限制。这些约束为癫痫网络的性质和癫痫发作的机制提供了重要的新假设。
