Wozny C, Gabriel S, Jandova K, Schulze K, Heinemann U, Behr J
Neuroscience Research Center of the Charité, Humboldt University Berlin, Schumannstr. 20/21, 10117 Berlin, Germany.
Neurobiol Dis. 2005 Aug;19(3):451-60. doi: 10.1016/j.nbd.2005.01.016.
Layer III neurons of the medial entorhinal cortex (mEC) project to CA1 via the temporoammonic pathway and exert a powerful feed-forward inhibition of CA1 pyramidal neurons. The present study evaluates the hypothesis that disrupted inhibition of CA1 pyramidal neurons causes an eased propagation of entorhinal seizures to the hippocampus via the temporoammonic pathway. Using a method to induce a confined epileptic focus in brain slices, we investigated the spread of epileptiform activity from the disinhibited mEC to CA1 in control and pilocarpine-treated rats that had displayed status epilepticus and spontaneous recurrent seizures. In pilocarpine-treated rats, the mEC showed a moderate layer III cell loss and an enhanced susceptibility to epileptiform discharges compared to control animals. Entorhinal discharges propagated to CA1 in pilocarpine-treated rats but not in controls. Disconnecting CA3 from CA1 did not affect the spread of epileptiform activity to CA1 excluding its propagation via the trisynaptic hippocampal loop. Mimicking the invasion of epileptiform discharges by repetitive stimulation of the temporoammonic pathway caused a facilitation of field potentials in CA1 that were contaminated by population spikes and afterdischarges in pilocarpine-treated but not control rats. Single cell recordings of CA1 pyramidal neurons revealed a dramatic loss of feed-forward inhibition and the occurrence of strong postsynaptic excitatory potentials in pilocarpine-treated rats. Excitatory responses in CA1 were characterized by multiple NMDA receptor-mediated afterdischarges and a strong paired-pulse facilitation in response to activation of the temporoammonic pathway. Our results suggest that, irrespective of the enhanced seizure-susceptibility of the mEC in epileptic rats, the loss of feed-forward inhibition and the enhanced NMDA receptor-mediated excitability CA1 pyramidal cells ease the spread of epileptiform activity from the mEC to CA1 via the temporoammonic pathway bypassing the classical trisynaptic hippocampal loop.
内嗅皮层（mEC）的III层神经元通过颞叶-海马通路投射至CA1，并对CA1锥体细胞施加强大的前馈抑制。本研究评估了以下假说：对CA1锥体细胞的抑制作用中断会导致内嗅性癫痫发作通过颞叶-海马通路更容易传播至海马体。我们使用一种在脑片中诱导局限性癫痫病灶的方法，研究了在已出现癫痫持续状态和自发性反复癫痫发作的对照大鼠和毛果芸香碱处理的大鼠中，癫痫样活动从去抑制的mEC传播至CA1的情况。与对照动物相比，毛果芸香碱处理的大鼠中，mEC表现出III层细胞中度丢失以及对癫痫样放电的易感性增强。内嗅放电在毛果芸香碱处理的大鼠中传播至CA1，但在对照大鼠中则不然。将CA3与CA1分离并不影响癫痫样活动向CA1的传播，排除了其通过三突触海马环路的传播。通过重复刺激颞叶-海马通路模拟癫痫样放电的侵入，导致毛果芸香碱处理的大鼠而非对照大鼠的CA1中出现场电位增强，该场电位被群体峰电位和后放电所污染。CA1锥体细胞的单细胞记录显示，毛果芸香碱处理的大鼠中前馈抑制显著丧失，且出现强烈的突触后兴奋性电位。CA1中的兴奋性反应以多个NMDA受体介导的后放电以及对颞叶-海马通路激活的强烈双脉冲易化为特征。我们的结果表明，无论癫痫大鼠中mEC癫痫易感性增强如何，前馈抑制的丧失以及CA1锥体细胞中NMDA受体介导的兴奋性增强，都会使癫痫样活动通过颞叶-海马通路绕过经典的三突触海马环路，更容易从mEC传播至CA1。
