Metabotropic glutamate receptor 1 activity generates persistent, N-methyl-d-aspartate receptor-dependent depression of hippocampal pyramidal cell excitability
Metabotropic glutamate receptor 1 activity generates persistent, N-methyl-d-aspartate receptor-dependent depression of hippocampal pyramidal cell excitability
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DOI：
10.1111/j.1460-9568.2009.06780.x
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发表时间：
2009-06-01
影响因子：
3.4
通讯作者：
Brown, J. T.
中科院分区：
文献类型：
--
作者：
Clement, J. P.;Randall, A. D.;Brown, J. T.
代谢型谷氨酸受体 (mGluR) 参与多种形式的神经元可塑性。在海马体中，它们在突触和内在可塑性的持久形式中具有明确的作用。在这里，我们描述了一种新形式的持久内在可塑性，我们称之为（S）-3,5-二羟基苯基甘氨酸（DHPG）介导的长期兴奋性抑制（DHPG-LDE），它是在 I 组 mGluR 短暂药理激活后产生的。在海马切片的细胞外记录中，DHPG-LDE 表达为在暴露于 I 组 mGluR 激动剂 (S)-DHPG 4 分钟后 CA1 或 CA3 细胞中逆向复合动作电位 (cAP) 的长期抑制。 CA3 轴突中诱发的顺向纤维齐射也观察到类似的现象。在 CA1 金字塔的单细胞记录中，DHPG-LDE 表现为逆向动作电位生成持续失败。 DHPG-LDE 可以被 mGluR1 拮抗剂 (S)-(+)-a-amino-4-carboxy-2-methylbenacetic Acid (LY367385) 阻断，但不能被 mGluR5 抑制剂 2-methyl-6-(pheneneethynyl)pyridine HCl (MPEP) 阻断。尽管 DHPG-LDE 对 α-氨基-3-羟基-5-甲基-4-异恶唑-丙酸酯/红藻氨酸和 γ-氨基丁酸 (A) 受体拮抗剂不敏感，但可被 N-甲基-d-天冬氨酸 (NMDA) 受体拮抗剂阻断。类似地，在单细胞记录中，DHPG 介导的逆向尖峰故障被 NMDA 受体拮抗作用消除。 (S)-DHPG 洗脱后很长时间，DHPG-LDE 被 mGluR1 拮抗作用逆转。 (S)-DHPG 的 4 分钟应用也产生了 CA1 锥体细胞的 NMDA 受体依赖性持续去极化。这种去极化并不是 DHPG-LDE 的唯一原因，因为通过提高细胞外 K+ 引起的类似水平的去极化增加了 cAP 的幅度。 DHPG-LDE不涉及HCN通道或蛋白质合成，但被蛋白激酶C或酪氨酸磷酸酶阻断剂消除。
Metabotropic glutamate receptors (mGluRs) are involved in many forms of neuronal plasticity. In the hippocampus, they have well-defined roles in long-lasting forms of both synaptic and intrinsic plasticity. Here, we describe a novel form of long-lasting intrinsic plasticity that we call (S)-3,5-dihydroxyphenylglycine (DHPG)-mediated long-term depression of excitability (DHPG-LDE), and which is generated following transient pharmacological activation of group I mGluRs. In extracellular recordings from hippocampal slices, DHPG-LDE was expressed as a long-lasting depression of antidromic compound action potentials (cAPs) in CA1 or CA3 cells following a 4-min exposure to the group I mGluR agonist (S)-DHPG. A similar phenomenon was also seen for orthodromic fibre volleys evoked in CA3 axons. In single-cell recordings from CA1 pyramids, DHPG-LDE was manifest as persistent failures in antidromic action potential generation. DHPG-LDE was blocked by (S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), an antagonist of mGluR1, but not 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an mGluR5 inhibitor. Although insensitive to antagonists of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate/kainate and gamma-aminobutyric acid(A) receptors, DHPG-LDE was blocked by antagonists of N-methyl-d-aspartate (NMDA) receptors. Similarly, in single-cell recordings, DHPG-mediated antidromic spike failures were eliminated by NMDA receptor antagonism. Long after (S)-DHPG washout, DHPG-LDE was reversed by mGluR1 antagonism. A 4-min application of (S)-DHPG also produced an NMDA receptor-dependent persistent depolarization of CA1 pyramidal cells. This depolarization was not solely responsible for DHPG-LDE, because a similar level of depolarization elicited by raising extracellular K+ increased the amplitude of the cAP. DHPG-LDE did not involve HCN channels or protein synthesis, but was eliminated by blockers of protein kinase C or tyrosine phosphatases.