Long-term potentiation alters the modulator pharmacology of AMPA-type glutamate receptors.
Long-term potentiation alters the modulator pharmacology of AMPA-type glutamate receptors.
复制标题
长时程增强作用改变了 AMPA 型谷氨酸受体的调节药理学。
作者：
B. Lin;Fernando Brücher;L. Colgin;G. Lynch
AMPA型谷氨酸受体生物物理性质的改变被认为是介导长时程增强(LTP)表达的机制之一。本研究测试了AMPA受体调节剂是否如这一假说所预测的那样，对增强的突触电流和控制的突触电流产生不同的影响。全细胞记录来自成年大鼠海马片CA1区锥体神经元。对两组不同的Schaffer-侧支/连合突触诱发的兴奋性突触后电流(EPSCs)进行神经元内比较。在一组输入中用theta爆发式刺激诱导LTP，30分钟后输注作用于AMPA受体脱敏动力学的药物环噻嗪(CTZ)。给药前增强组EPSCs的衰变时间常数略短于对照组，但显著短于对照组。CTZ减缓了EPSCs的衰退，正如之前的研究所报道的那样，而且在增强的突触中这种作用要大得多。此外，与对照通路相比，注射CTZ对增强通路的幅度有更大的影响。LTP和CTZ之间的相互作用也是在一组单独的实验中获得的，在这些实验中，GABA受体拮抗剂被用来阻断抑制性突触后电流。此外，在CTZ存在的情况下，双脉冲易化没有显著变化，这表明该药物的突触前效应可以忽略不计。这些发现为LTP改变AMPA受体动力学提供了新的证据。使用AMPA受体动力学模型评估了导致LTP观察到的效应的变化的候选对象；简单地增加通道开放速率提供了与LTP数据最令人满意的匹配。
Changes in the biophysical properties of AMPA-type glutamate receptors have been proposed to mediate the expression of long-term potentiation (LTP). The present study tested if, as predicted from this hypothesis, AMPA receptor modulators differentially affect potentiated versus control synaptic currents. Whole cell recordings were collected from CA1 pyramidal neurons in hippocampal slices from adult rats. Within-neuron comparisons were made of the excitatory postsynaptic currents (EPSCs) elicited by two separate groups of Schaffer-collateral/commissural synapses. LTP was induced by theta burst stimulation in one set of inputs; cyclothiazide (CTZ), a drug that acts on the desensitization kinetics of AMPA receptors, was infused 30 min later. The decay time constants of the potentiated EPSCs prior to drug infusion were slightly, but significantly, shorter than those of control EPSCs. CTZ slowed the decay of the EPSCs, as reported in prior studies, and did so to a significantly greater degree in the potentiated synapses. Additionally, infusion of CTZ resulted in significantly greater effects on amplitude in potentiated pathways as compared with control pathways. The interaction between LTP and CTZ was also obtained in a separate set of experiments in which GABA receptor antagonists were used to block inhibitory postsynaptic currents. Additionally, there was no significant change in paired-pulse facilitation in the presence of CTZ, indicating that presynaptic effects of the drug were negligible. These findings provide new evidence that LTP modifies AMPA receptor kinetics. Candidates for the changes responsible for the observed effects of LTP were evaluated using a model of AMPA receptor kinetics; a simple increase in the channel opening rate provided the most satisfactory match with the LTP data.
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56.9
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