Astrocytic glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices
Astrocytic glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices
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DOI：
10.1523/jneurosci.2836-06.2006
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发表时间：
2006-09-06
影响因子：
5.3
通讯作者：
Haydon, Philip G.
中科院分区：
文献类型：
--
作者：
Fellin, Tommaso;Gomez-Gonzalo, Marta;Haydon, Philip G.
星形胶质细胞释放谷氨酸激活海马锥体神经元同步慢向电流（SICs），该电流由NMDA受体介导，代表了一种促进神经元活动同步的非突触机制。最近的两项研究表明，SICs产生的神经元阵发性去极化类似于典型的癫痫样间期活动，并提出癫痫可能存在星形细胞基础（Kang et al., 2005; Tian et al., 2005）。我们使用两个体外海马切片癫痫样活动模型来验证这一假设。去除细胞外Mg2+，应用微毒素或灌注0.5 mM Mg2+和8.5 mM含K+的生理盐水，分别主要导致神经元发作和发作间样癫痫样活动。虽然这两种模型都能触发癫痫样活动，但星形胶质细胞Ca2+振荡仅在0 mM Mg2+和微毒素切片灌注后增加。星形细胞Ca2+信号的激活与SICs频率的增加有关，并且，当配对神经元彼此在100 μ m内并同步神经元Ca2+升高时，同步神经元去极化和动作电位放电的产生。TTX阻断发作期和发作期样癫痫活动，而不影响sic或sic介导的神经元同步。相比之下，阻断SICs的NMDA受体拮抗剂并不能阻止发作或发作间样事件的发生。基于这一明确的药理学，我们的数据表明，星形胶质细胞的非突触谷氨酸释放对体外癫痫样活动的产生不是必需的，尽管我们不能排除它可能调节癫痫样事件强度的可能性。
The release of glutamate from astrocytes activates synchronous slow inward currents (SICs) in hippocampal pyramidal neurons, which are mediated by the NMDA receptor and represent a nonsynaptic mechanism to promote the synchronization of neuronal activity. Two recent studies demonstrate that SICs generate neuronal paroxysmal depolarizations resembling those typical of interictal epileptiform activity and proposed that there could be an astrocytic basis of epilepsy (Kang et al., 2005; Tian et al., 2005). We tested this hypothesis using two in vitro models of epileptiform activity in hippocampal slices. Removal of extracellular Mg2+ and application of picrotoxin or perfusion with 0.5 mM Mg2+ and 8.5 mM K+-containing saline result mainly in neuronal ictal-and interictal-like epileptiform activity, respectively. Although both models trigger epileptiform activity, astrocytic Ca2+ oscillations were increased only after slice perfusion with 0 mM Mg2+ and picrotoxin. The activation of astrocytic Ca2+ signaling correlates with an increased frequency of SICs, and, when paired neurons were within 100 mu m of one another with synchronous neuronal Ca2+ elevations, the generation of synchronous neuronal depolarizations and action potential discharges. TTX blocked both ictal-and interictal-like epileptiform activity without affecting SICs or SIC-mediated neuronal synchronization. In contrast, NMDA receptor antagonists, which block SICs, did not prevent the generation of either ictal-or interictal-like events. Based on this clear-cut pharmacology, our data demonstrate that nonsynaptic glutamate release from astrocytes is not necessary for the generation of epileptiform activity in vitro, although we cannot exclude the possibility that it may modulate the strength of the ictal (seizure)-like event.