There is uncertainty regarding when and which groups of neurons fire synchronously during seizures. While several studies found heterogeneous firing during seizures, others suggested synchronous neuronal firing in the seizure core. We tested whether neuronal activity during seizures is orderly in the direction of the excitatory neuronal connections in the circuit. There are strong excitatory connections laterally within the septotemporally organized lamella and inhibitory trans-lamellar connections in the hippocampus, which allow testing of the connectivity hypothesis. We further tested whether epileptogenesis enhances synchrony and antiseizure drug administration disrupts it. We recorded local field potentials from CA1 pyramidal neurons using a small microelectrode array and kindled rats by a rapid, recurrent hippocampal stimulation protocol. We compared cross-correlation, theta phase synchronization, entropy, and event synchronization. These analyses revealed that the firing pattern was correlated along the lamellar, but not the septotemporal, axis during evoked seizures. During kindling, neuronal synchrony increased along the lamellar axis, while synchrony along the septotemporal axis remained relatively low. Additionally, the theta phase distribution demonstrated that CA1 pyramidal cell firing became preferential for theta oscillation negative peak as kindling progressed in the lamellar direction but not in the trans-lamellar direction. Last, event synchronization demonstrated that neuronal firings along the lamellar axis were more synchronized than those along the septotemporal axis. There was a marked decrease in synchronization and phase preference after treatment with phenytoin and levetiracetam. The synchrony structure of CA1 pyramidal neurons during seizures and epileptogenesis depends on anatomic connectivity and plasticity.

SIGNIFICANCE STATEMENT We could improve the efficacy of brain stimulation to treat seizures by understanding the structure of synchrony. Electrical stimulation may disrupt seizures by desynchronizing neurons, but there is an uncertainty on which groups of neurons fire synchronously or chaotically during seizures. Here, we demonstrate that neurons linked by excitatory connections fire synchronously during seizures, and this synchrony is modulated by epileptogenesis and antiseizure drugs. Closed-loop brain stimulation carefully targeted to disrupt synchrony may improve the treatment of seizures.

在癫痫发作期间，关于何时以及哪些神经元组同步激发存在不确定性。虽然几项研究发现癫痫发作期间存在异质放电，但其他研究表明癫痫发作核心中的神经元同步放电。我们测试了癫痫发作期间的神经元活动是否朝着电路中兴奋性神经元连接的方向有序。在海马体中间隔时间组织的板层和抑制性跨板层连接中存在横向的强烈兴奋性连接，这允许测试连接性假设。我们进一步测试了癫痫发生是否增强了同步性，而抗癫痫药物的给药是否会破坏它。我们使用小型微电极阵列记录了来自 CA1 锥体神经元的局部场电位，并通过快速、反复的海马刺激方案点燃了大鼠。我们比较了互相关、θ 相位同步、熵和事件同步。这些分析表明，在诱发性癫痫发作期间，放电模式与板层相关，但与中隔颞轴无关。在点燃期间，神经元同步沿层状轴增加，而沿 septotemporal 轴的同步性保持相对较低。此外，theta 相位分布表明，随着点燃在层状方向而不是在跨层方向上进行，CA1 锥体细胞放电变得优先于θ振荡负峰。最后，事件同步表明沿层状轴的神经元放电比沿 septotemporal 轴的神经元放电更同步。苯妥英和左乙拉西坦治疗后同步性和相位偏好显着降低。CA1 锥体神经元在癫痫发作和癫痫发生过程中的同步结构取决于解剖连接和可塑性。

意义声明我们可以通过了解同步结构来提高脑刺激治疗癫痫发作的疗效。电刺激可能会通过使神经元不同步来扰乱癫痫发作，但在癫痫发作期间哪些神经元组同步或无序激发存在不确定性。在这里，我们证明了通过兴奋性连接连接的神经元在癫痫发作期间同步激发，并且这种同步性受到癫痫发生和抗癫痫药物的调节。仔细针对破坏同步的闭环脑刺激可能会改善癫痫发作的治疗。