Blockade of GABA synthesis only affects neural excitability under activated conditions in rat hippocampal slices
Blockade of GABA synthesis only affects neural excitability under activated conditions in rat hippocampal slices
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DOI：
10.1016/j.neuint.2008.04.006
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发表时间：
2008-07-01
影响因子：
4.2
通讯作者：
Williamson, Anne
中科院分区：
文献类型：
--
作者：
Dericioglu, Nese;Garganta, Cheryl L.;Williamson, Anne
本研究的主要目标是确定 GABA 合成的抑制是否足以在大鼠海马切片模型中诱导网络过度兴奋，与 GABA 受体阻断所观察到的情况相当。我们使用大鼠海马切片 CA1 区域的现场和细胞内记录来确定用惊厥剂 3-巯基丙酸 (MPA) 阻断 GABA 合成的生理效应。我们使用 2-13C-葡萄糖作为标记源并采用液相色谱-串联质谱法测量了切片中 GABA 和谷氨酸的合成率。在对照记录条件下，3.5 mM MPA 对诱发事件影响很小。经过一系列刺激后，组织兴奋性得到增强；当 GABA 转运被阻断时，这种效应会增强。重复刺激和 MPA 后诱发抑制电位 (IPSP) 失效。当细胞外钾升高 (5 mM) 时，可以可靠地观察到自发性癫痫样活动。单独使用 MPA 时，GABA 合成减少 49%；使用 MPA 和过量钾时，GABA 合成减少 45%； GABA 含量没有显着改变。我们的数据表明：（1）在没有网络激活的情况下，MPA 不会显着损害 GABA 能抑制； (2) GABA能突触抑制是由新合成的GABA介导的； (3) 存在一个可耗尽的 GABA 池，当在基础而非激活条件下合成受损时，可以维持 GABA 能抑制； (4) 仅当新合成的 GABA 水平较低时才会出现明显的过度兴奋。 (c) 2008 Elsevier Ltd. 保留所有权利。
The primary goal of this study was to establish whether inhibition of GABA synthesis was sufficient to induce network hyperexcitability in a rat hippocampal slice model comparable to that seen with GABA receptor blockade. We used field and intracellular recordings from the CA1 region of rat hippocampal slices to determine the physiological effects of blocking GABA synthesis with the convulsant, 3-mercaptoproprionic acid (MPA). We measured the rate of synthesis of GABA and glutamate in slices using 2-13C-glucose as a label source and liquid chromatography-tandem mass spectrometry. There was little effect of 3.5 mM MPA on evoked events under control recording conditions. Tissue excitability was enhanced following a series of stimulus trains; this effect was enhanced when GABA transport was blocked. Evoked inhibitory potentials (IPSPs) failed following repetitive stimulation and MPA. Spontaneous epileptiform activity was seen reliably with elevated extracellular potassium (5 mM). GABA synthesis decreased by 49% with MPA alone and 45% with the combination of MPA and excess potassium; GABA content was not substantially altered. Our data indicate: (1) GABAergic inhibition cannot be significantly compromised by MPA without network activation; (2) GABAergic synaptic inhibition is mediated by newly synthesized GABA; (3) there is a depletable pool of GABA that can sustain GABAergic inhibition when synthesis is impaired under basal, but not activated conditions; (4) overt hyperexcitability is only seen when newly synthesized GABA levels are low. (c) 2008 Elsevier Ltd. All rights reserved.