ZD7288 inhibits postsynaptic glutamate receptor-mediated responses at hippocampal perforant path-granule cell synapses
ZD7288 inhibits postsynaptic glutamate receptor-mediated responses at hippocampal perforant path-granule cell synapses
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DOI：
10.1111/j.0953-816x.2003.03174.x
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发表时间：
2004-02-01
影响因子：
3.4
通讯作者：
Chen, C
中科院分区：
文献类型：
--
作者：
Chen, C
超极化激活通道（Hyperpolarization-activated channels，I（h））在神经系统中广泛表达，被认为在调节膜兴奋性和节律性活动中起重要作用。最近的证据表明，Ih可能参与海马的长时程增强（LTP），然而，结果是有争议的。为了探讨这些不同结果的可能原因，在小鼠海马切片中评估了I（h）阻断剂对突触活性的影响。ZD 7288（20 μ m），一种选择性I（h）阻断剂，明显阻止了LTP的诱导，而Cs（+）（1 mM），一种常用的I（h）阻断剂，对海马穿孔通路-齿状颗粒细胞突触的LTP没有影响。此外，ZD 7288而不是Cs（+）废除了基础突触传递。电压钳实验结果表明，ZD 7288对超极化激活电流的抑制作用很小，表明颗粒神经元中Ih的表达较弱。由外向外的斑贴记录显示，ZD 7288抑制谷氨酸受体介导的反应，而Cs（+）对它们没有影响。同时，ZD 7288降低α-氨基-3-羟基-5-甲基异恶唑-4-丙酸酯和N-甲基-D-天冬氨酸受体介导的兴奋性突触后电流。结果表明，ZD 7288诱导的突触传递减少可能是由于其抑制齿状颗粒神经元上的突触后谷氨酸受体。
Hyperpolarization-activated channels (I(h)) are widely expressed in the nervous system and believed to play an important role in the regulation of membrane excitability and rhythmic activity. Recent evidence suggests that Ih may be involved in long-term potentiation (LTP) in the hippocampus; however, the results are controversial. To explore the possible causes of these differing results, the effects of I(h) blockers on synaptic activity were evaluated in mouse hippocampal slices. ZD7288 (20 mum), a selective I(h) blocker, apparently prevented the induction of LTP, while Cs(+) (1 mM), a commonly used I(h) blocker, had no effect on LTP at hippocampal perforant path-dentate granule cell synapses. In addition, ZD7288 but not Cs(+) abolished basal synaptic transmission. Results from voltage-clamp experiments showed that ZD7288 produced a very little inhibition on hyperpolarization-activated currents, indicating a weak expression of the Ih in granule neurons. Outside-out patch recordings revealed that ZD7288 inhibited glutamate receptor-mediated responses, while Cs(+) had no effect on them. Meanwhile, ZD7288 reduced both alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents. The results suggest that ZD7288-induced reduction of synaptic transmission may result from its inhibition of the postsynaptic glutamate receptors on dentate granule neurons.