Activation of 5-HT7 Serotonin Receptors Reverses Metabotropic Glutamate Receptor-Mediated Synaptic Plasticity in Wild-Type and Fmr1 Knockout Mice, a Model of Fragile X Syndrome
Activation of 5-HT7 Serotonin Receptors Reverses Metabotropic Glutamate Receptor-Mediated Synaptic Plasticity in Wild-Type and Fmr1 Knockout Mice, a Model of Fragile X Syndrome
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DOI：
10.1016/j.biopsych.2012.06.008
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发表时间：
2012-12-01
影响因子：
10.6
通讯作者：
Ciranna, Lucia
中科院分区：
文献类型：
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作者：
Costa, Lara;Spatuzza, Michela;Ciranna, Lucia
背景：脆性X综合征（FXS）是智力残疾和自闭症的遗传原因。FXS的动物模型Fmr 1敲除（Fmr 1 KO）小鼠表现出空间记忆障碍和海马中的突触功能障碍，并伴有由代谢型谷氨酸受体（mGluR-LTD）介导的长期抑郁的异常增强。神经递质5-羟色胺（5-HT）通过5-羟色胺1A（5-HT 1A）和5-羟色胺7（5-HT 7）受体调节海马依赖性学习;其潜在机制尚不清楚。我们采用电生理学方法检测了5-HT对野生型和Fmr 1基因敲除小鼠mGluR-LTD的影响，并采用免疫细胞化学和生物素化方法研究了2-氨基-3-结果：应用5-HT或8-OH-DPAT（5-HT 1A/5-HT 7混合激动剂）可逆转海马脑片mGluR-LTD。8-OH-DPAT对mGluR-LTD的抑制作用在5-HT 1A受体拮抗剂WAY-100635存在下持续存在，被SB-269970（5-HT 7受体拮抗剂）消除，并被新型选择性5-HT 7受体激动剂LP-211模拟。一致地，8-OH-DPAT降低mGluR介导的海马切片和培养的海马神经元中AMPA谷氨酸受体2（GluR 2）亚单位表面表达的降低，LP-211模拟了该作用，SB-269970阻断了该作用。在Fmr 1 KO小鼠中，mGluR-LTD异常增强;与野生型相似，8-OH-DPAT逆转mGluR-LTD并减少mGluR诱导的表面AMPA受体减少，SB-269970拮抗了这种作用。5-羟色胺7受体激活逆转了野生型和Fmr 1 KO小鼠中代谢型谷氨酸受体诱导的AMPA受体内化和LTD，纠正了过量的mGluR-LTD。5-HT 7受体的选择性激活可能代表FXS治疗中的新策略。
Background: Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) receptors; the underlying mechanisms are unknown.Methods: We used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochemistry and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) glutamate receptor surface expression.Results: Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated reduction of AMPA glutamate receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced reduction of surface AMPA receptors, an effect antagonized by SB-269970.Conclusions: Serotonin 7 receptor activation reverses metabotropic glutamate receptor-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS.