Synaptic depolarizing GABA response in adults is excitatory and proconvulsive when GABAB receptors are blocked
Synaptic depolarizing GABA response in adults is excitatory and proconvulsive when GABAB receptors are blocked
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DOI：
10.1152/jn.01026.2004
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发表时间：
2005-05-01
影响因子：
2.5
通讯作者：
Perkins, KL
中科院分区：
文献类型：
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作者：
Kantrowitz, JT;Francis, NN;Perkins, KL
在4-氨基吡啶的存在下，中间神经元同步放电，在成年豚鼠海马脑片的CA 3锥体细胞中引起巨大的GABA介导的突触后电位（GPSP;电压钳中的GPSC）。这些三相GPSP由GABA（A）介导的超极化组分、去极化组分和GABA（B）介导的超极化组分组成。我们认为GABA（B）受体对突触后去极化GABA反应起控制作用。微电极和细胞贴附记录表明，在存在GABA（B）受体拮抗剂（2S）-3-[[（1 S）-1-（3，4-二氯苯基）乙基]氨基-2-羟丙基]（苯甲基）次膦酸（CGP 55845 A; P = 0.003和0.0005，分别）的情况下，GPSP去极化组分期间的平均动作电位数显著增加。全细胞电压钳记录显示，突触后GABA（B）和去极化GABA成分的GPSC基本重叠，允许GABA（B）介导的超极化抑制兴奋介导的去极化GABA成分。进一步的电压钳记录显示，CGP 55845 A增加了GPSC的去极化GABA组分的持续时间，即使GABA（B）组分已经被内部QX-314阻断，这表明CGP 55845 A也增加了GABA释放的持续时间。当癫痫能传递完整时，GPSP直接先于癫痫样后放电。我们假设GPSP的去极化成分触发癫痫样事件，并在此显示CGP 55845 A增强去极化成分增加癫痫样活动。CGP 55845 A使GPSP触发癫痫样事件的可能性从32%增加到99%（P = 0.0000001），并显著增加了每次癫痫样事件的后放电次数（P = 0.001）。GABA（B）受体功能丧失与啮齿动物和人类颞叶癫痫相关。我们发现GABA（B）受体控制突触去极化GABA反应，阻断GABA（B）受体可使去极化GABA反应兴奋并诱发惊厥。
In the presence of 4-aminopyridine, interneurons fire synchronously, causing giant GABA-mediated postsynaptic potentials (GPSPs; GPSCs in voltage clamp) in CA3 pyramidal cells in hippocampal slices from adult guinea pigs. These triphasic GPSPs are composed of a GABA(A)-mediated hyperpolarizing component, a depolarizing component, and a GABA(B)-mediated hyperpolarizing component. We propose that GABA(B) receptors exert control over the postsynaptic depolarizing GABA response. Microelectrode and cell-attached recordings demonstrated that the mean number of action potentials during the depolarizing component of the GPSP increased dramatically in the presence of the GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid (CGP 55845A; P = 0.003 and 0.0005, respectively). Whole cell voltage-clamp recordings showed that the postsynaptic GABA(B) and depolarizing GABA components of the GPSC overlap substantially, allowing the GABA(B)-mediated hyperpolarization to suppress the excitation mediated by the depolarizing GABA component. Further voltage-clamp recordings showed that CGP 55845A increased the duration of the depolarizing GABA component of the GPSC even when the GABA(B) component had already been blocked by internal QX-314, suggesting that CGP 55845A also increased the duration of GABA release. When glutamatergic transmission is intact, GPSPs directly precede epileptiform afterdischarges. We hypothesize that the depolarizing component of the GPSP triggers the epileptiform events and show here that enhancement of the depolarizing component with CGP 55845A increased epileptiform activity. CGP 55845A increased the likelihood of a GPSP triggering an epileptiform event from 32 to 99% (P = 0.0000001), and significantly increased the number of afterdischarges per epileptiform event (P = 0.001). Loss of GABA(B) receptor function is associated with temporal lobe epilepsy in rodents and humans. We show here that GABA(B) receptors exert control over the synaptic depolarizing GABA response and that block of GABA(B) receptors makes the depolarizing GABA response excitatory and proconvulsive.