Costa Lara, Sardone Lara M, Lacivita Enza, Leopoldo Marcello, Ciranna Lucia
Department of Clinical and Experimental Medicine, University of Messina Messina, Italy.
Department of Biomedical and Biotechnological Sciences, University of Catania Catania, Italy.
Front Behav Neurosci. 2015 Mar 12;9:65. doi: 10.3389/fnbeh.2015.00065. eCollection 2015.
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.
血清素5-HT7受体在海马体中表达，并调节海马神经元的兴奋性。我们之前已经表明，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，我们已经表明，在野生型（wt）和脆性X综合征小鼠模型Fmr1基因敲除（KO）小鼠中，5-HT7受体的激活逆转了代谢型谷氨酸受体介导的长期抑郁（mGluR-LTD），在该小鼠模型中mGluR-LTD异常增强，这表明5-HT7受体激动剂可能被设想为治疗脆性X综合征的一种新的治疗策略。从这个角度来看，我们已经对具有高结合亲和力和对5-HT7受体选择性的新型分子的基本体外药代动力学特性进行了表征，并且我们已经使用急性海马脑片上的膜片钳技术测试了它们对突触可塑性的影响。在这里我们表明，LP-211，一种5-HT7受体的高亲和力选择性激动剂，在wt和Fmr1 KO小鼠中逆转了mGluR-LTD，纠正了脆性X综合征小鼠模型中的突触功能障碍。在新型5-HT7受体假定激动剂中，化合物BA-10相对于LP-211显示出对5-HT7受体的亲和力和选择性提高，以及体外药代动力学特性改善。BA-10在wt和Fmr1 KO小鼠的CA3-CA1突触中显著逆转了mGluR-LTD，表明BA-10表现为5-HT7受体的高效激动剂，并在脆性X综合征小鼠模型中减少了过度的mGluR-LTD。另一方面，分别由LP-211和BA-10的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它们不作为5-HT7受体的激动剂。目前的结果提供了关于新型5-HT7受体激动剂的构效关系的信息，并表明LP-211和BA-10可能用作治疗脆性X综合征的新型药理学工具。
