Departments of Neuroscience and Pharmacology, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University Irving Medical Center, New York, NY 10027, USA.
The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Neuron. 2022 Oct 5;110(19):3121-3138.e8. doi: 10.1016/j.neuron.2022.07.020. Epub 2022 Aug 19.
The hippocampal CA2 region, an area important for social memory, has been suspected to play a role in temporal lobe epilepsy (TLE) because of its resistance to degeneration observed in neighboring CA1 and CA3 regions in both humans and rodent models of TLE. However, little is known about whether alterations in CA2 properties promote seizure generation or propagation. Here, we addressed the role of CA2 using the pilocarpine-induced status epilepticus model of TLE. Ex vivo electrophysiological recordings from acute hippocampal slices revealed a set of coordinated changes that enhance CA2 PC intrinsic excitability, reduce CA2 inhibitory input, and increase CA2 excitatory output to its major CA1 synaptic target. Moreover, selective chemogenetic silencing of CA2 pyramidal cells caused a significant decrease in the frequency of spontaneous seizures measured in vivo. These findings provide the first evidence that CA2 actively contributes to TLE seizure activity and may thus be a promising therapeutic target.
海马体 CA2 区域对于社会记忆很重要，由于在人类和颞叶癫痫（TLE）的啮齿动物模型中，其邻近的 CA1 和 CA3 区域观察到抗退化现象，因此被怀疑在 TLE 中发挥作用。然而，对于 CA2 特性的改变是否促进癫痫发作或传播知之甚少。在这里，我们使用匹罗卡品诱导的 TLE 癫痫持续状态模型来研究 CA2 的作用。急性海马切片的离体电生理记录显示了一系列协调的变化，这些变化增强了 CA2 PC 的内在兴奋性，减少了 CA2 的抑制性输入，并增加了 CA2 对其主要 CA1 突触靶标的兴奋性输出。此外，CA2 锥体神经元的选择性化学遗传沉默导致体内测量的自发性癫痫发作频率显著降低。这些发现首次提供了 CA2 积极参与 TLE 癫痫活动的证据，因此可能是一个有前途的治疗靶点。
