Ayala Jennifer E, Niswender Colleen M, Luo Qingwei, Banko Jessica L, Conn P Jeffrey
Department of Pharmacology, Program in Translational Neuropharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Neuropharmacology. 2008 Apr;54(5):804-14. doi: 10.1016/j.neuropharm.2007.12.009. Epub 2007 Dec 24.
Group III metabotropic glutamate receptors (mGluRs) reduce synaptic transmission at the Schaffer collateral-CA1 (SC-CA1) synapse in rats by a presynaptic mechanism. Previous studies show that low concentrations of the group III-selective agonist, L-AP4, reduce synaptic transmission in slices from neonatal but not adult rats, whereas high micromolar concentrations reduce transmission in both age groups. L-AP4 activates mGluRs 4 and 8 at much lower concentrations than those required to activate mGluR7, suggesting that the group III mGluR subtype modulating transmission is a high affinity receptor in neonates and a low affinity receptor in adults. The previous lack of subtype selective ligands has made it difficult to test this hypothesis. We have measured fEPSPs in the presence of novel subtype selective agents to address this question. We show that the effects of L-AP4 can be blocked by LY341495 in both neonates and adults, verifying that these effects are mediated by mGluRs. In addition, the selective mGluR8 agonist, DCPG, has a significant effect in slices from neonatal rats but does not reduce synaptic transmission in adult slices. The mGluR4 selective allosteric potentiator, PHCCC, is unable to potentiate the L-AP4-induced effects at either age. Taken together, our data suggest that group III mGluRs regulate transmission at the SC-CA1 synapse throughout development but there is a developmental regulation of the subtypes involved so that both mGluR7 and mGluR8 serve this role in neonates whereas mGluR7 is involved in regulating transmission at this synapse throughout postnatal development.
III 组代谢型谷氨酸受体（mGluRs）通过一种突触前机制降低大鼠海马体中沙菲氏侧枝 - CA1（SC - CA1）突触的突触传递。先前的研究表明，低浓度的 III 组选择性激动剂 L - AP4 可降低新生大鼠脑片而非成年大鼠脑片的突触传递，而高微摩尔浓度则可降低两个年龄组的突触传递。L - AP4 激活 mGluRs 4 和 8 的浓度远低于激活 mGluR7 所需的浓度，这表明在新生大鼠中调节突触传递的 III 组 mGluR 亚型是高亲和力受体，而在成年大鼠中是低亲和力受体。此前缺乏亚型选择性配体使得难以验证这一假设。我们在新型亚型选择性试剂存在的情况下测量了场兴奋性突触后电位（fEPSPs）以解决这个问题。我们发现，LY341495 可在新生大鼠和成年大鼠中阻断 L - AP4 的作用，证实这些作用是由 mGluRs 介导的。此外，选择性 mGluR8 激动剂 DCPG 在新生大鼠脑片中具有显著作用，但不会降低成年大鼠脑片的突触传递。mGluR4 选择性变构增强剂 PHCCC 在两个年龄组中均无法增强 L - AP4 诱导的效应。综上所述，我们的数据表明，III 组 mGluRs 在整个发育过程中调节 SC - CA1 突触的传递，但所涉及的亚型存在发育调控，使得 mGluR7 和 mGluR8 在新生大鼠中均发挥此作用，而 mGluR7 在出生后发育过程中参与调节该突触的传递。
