Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype
Study of Novel Selective mGlu2 Agonist in the Temporo-Ammonic Input to CA1 Neurons Reveals Reduced mGlu2 Receptor Expression in a Wistar Substrain with an Anxiety-Like Phenotype
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DOI：
10.1523/jneurosci.0418-11.2011
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发表时间：
2011-05-04
影响因子：
5.3
通讯作者：
Lodge, David
中科院分区：
文献类型：
--
作者：
Ceolin, Laura;Kantamneni, Sriharsha;Lodge, David
II组代谢型受体（mGluRs）通过调节神经递质释放来调节中枢突触传递。然而，缺乏区分mGlu 2和mGlu 3受体的药理学工具，阻碍了这两种受体亚型的作用的鉴定。本实验用mGlu_2受体激动剂和mGlu_3受体拮抗剂LY 395756 [（1 SR，2SR，4 RS，5 RS，6SR）-2-amino-4-methylbicyclo[3.1.0]-hexane 2，6-dicarboxyl]，研究了这两种受体在大鼠海马脑片内嗅皮层至CA_1-腔隙分子层的颞-氨通路中的作用。令人惊讶的是，由LY 395756诱导的田间EPSP的抑制程度分为两个不同的组，EC（50）值为< 1 mu M and >100 μ M。在“敏感”切片中，LY 395756与混合mGlu 2/mGlu 3激动剂DCG-IV [（2S，2 'R，3' R）-2-（2 '，3'-dicarboxycyclopropyl）glycine]具有相加作用，而在“不敏感”切片中，LY 395756降低DCG-IV的作用，IC（50）类似于1 μ M。这种敏感和不敏感切片的分离可以通过LY 395756分别作为mGlu 2激动剂和mGlu 3拮抗剂来解释，这一发现得到了缺乏这些受体的小鼠的数据的支持。的异质性与差异表达水平的mGlu 2受体在我们的Wistar殖民地和其他Wistar亚株。对行为相关性的初步研究表明，缺乏mGlu 2受体的大鼠在旷场和高架十字迷宫试验中表现出焦虑样行为。这些发现对精神疾病的大鼠模型有意义，特别是考虑到mGlu 2受体是正在开发的焦虑化合物的靶点。
Group II metabotropic receptors (mGluRs) regulate central synaptic transmission by modulating neurotransmitter release. However, the lack of pharmacological tools differentiating between mGlu2 and mGlu3 receptors has hampered identification of the roles of these two receptor subtypes. We have used LY395756 [(1SR,2SR,4RS,5RS,6SR)-2-amino-4-methylbicyclo[3.1.0]-hexane2,6-dicarboxylic], an agonist at mGlu2 receptors and an antagonist at mGlu3 receptors in cell lines, to investigate the roles of these receptors in the temporo-ammonic path from entorhinal cortex to CA1-stratum lacunosum moleculare in rat hippocampal slices. Surprisingly, the degree of inhibition of the field EPSP induced by LY395756 fell into two distinct groups, with EC(50) values of < 1 mu M and > 100 mu M. In "sensitive" slices, LY395756 had additive actions with a mixed mGlu2/mGlu3 agonist, DCG-IV [(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine], whereas in "insensitive" slices, LY395756 reduced the effect of DCG-IV, with an IC(50) of similar to 1 mu M. This separation into sensitive and insensitive slices could be explained by LY395756 acting as an mGlu2 agonist and mGlu3 antagonist, respectively, a finding supported by data from mice lacking these receptors. The heterogeneity was correlated with differences in expression levels of mGlu2 receptors within our Wistar colony and other Wistar substrains. The initial search for a behavioral correlate indicated that rats lacking mGlu2 receptors showed anxiety-like behavior in open-field and elevated plus maze assays. These findings have implications for rat models of psychiatric disease and are especially pertinent given that mGlu2 receptors are targets for compounds under development for anxiety.