Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome.
Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome.
复制标题
DOI：
10.3389/fnbeh.2015.00065
复制
发表时间：
2015
影响因子：
3
通讯作者：
Ciranna L
中科院分区：
文献类型：
--
作者：
Costa L;Sardone LM;Lacivita E;Leopoldo M;Ciranna L
5-羟色胺5-HT7受体在海马中表达并调节海马神经元的兴奋性。我们之前已经证明5-HT7受体调节谷氨酸介导的海马突触传递和长期突触可塑性。特别是，我们已经证明，在野生型（wt）和Fmr1 KO小鼠（脆性X综合征小鼠模型中，mGluR-LTD异常增强）中，5-HT7受体的激活逆转了代谢性谷氨酸受体介导的长期抑郁（mGluR-LTD），这表明5-HT7受体激动剂可能被设想为脆性X综合征的一种新的治疗策略。从这个角度来看，我们已经表征了对5-HT7受体具有高结合亲和力和选择性的新分子的基本体外药代动力学特性，并使用膜片钳在急性海马切片上测试了它们对突触可塑性的影响。在这里，我们发现LP-211，一种高亲和力的5-HT7受体选择性激动剂，在wt和Fmr1 KO小鼠中逆转mGluR-LTD，纠正脆性X综合征小鼠模型中的突触功能障碍。在新的推测的5-HT7受体激动剂中，化合物BA-10对5-HT7受体具有更好的亲和力和选择性，并且相对于LP-211具有更好的体外药代动力学特性。BA-10可显著逆转wt和Fmr1KO小鼠CA3-CA1突触中的mGluR-LTD，表明BA-10是一种高效的5-HT7受体激动剂，可降低脆性X综合征小鼠模型中过度的mGluR-LTD。另一方面，分别由LP-211和BA-10体内代谢产生的化合物RA-7和PM-20对mGluR-LTD没有影响，因此在我们的条件下不表现为5-HT7受体的激动剂。本研究结果为新型5-HT7受体激动剂的构效关系提供了信息，并提示LP-211和BA-10可能作为治疗脆性X综合征的新型药理工具。
Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of Fragile X Syndrome.
登录
查看更多内容
DOI：
10.1073/pnas.1013855108
发表时间：
2011-02-08
影响因子：
11.1
作者：
Krueger, Dilja D.;Osterweil, Emily K.;Bear, Mark F.
通讯作者：
Bear, Mark F.
影响因子：
2.4
作者：
Hooper, Stephen R.;Hatton, Deborah;Bailey, Donald B., Jr.
通讯作者：
Bailey, Donald B., Jr.
影响因子：
8.2
作者：
D'Antoni S;Spatuzza M;Bonaccorso CM;Musumeci SA;Ciranna L;Nicoletti F;Huber KM;Catania MV
通讯作者：
Catania MV
影响因子：
2.5
作者：
Hedlund, Peter B.;Leopoldo, Marcello;Perrone, Roberto
通讯作者：
Perrone, Roberto
影响因子：
10.6
作者：
Costa, Lara;Spatuzza, Michela;Ciranna, Lucia
通讯作者：
Ciranna, Lucia