Boda Bernadett, Mendez Pablo, Boury-Jamot Benjamin, Magara Fulvio, Muller Dominique
Department of Basic Neurosciences, School of Medicine, University of Geneva, Geneva 4 1211, Switzerland.
Eur J Neurosci. 2014 Apr;39(7):1130-7. doi: 10.1111/ejn.12488.
Fragile X syndrome (FXS) is characterized by intellectual disability and autistic traits, and results from the silencing of the FMR1 gene coding for a protein implicated in the regulation of protein synthesis at synapses. The lack of functional Fragile X mental retardation protein has been proposed to result in an excessive signaling of synaptic metabotropic glutamate receptors, leading to alterations of synapse maturation and plasticity. It remains, however, unclear how mechanisms of activity-dependent spine dynamics are affected in Fmr knockout (Fmr1-KO) mice and whether they can be reversed. Here we used a repetitive imaging approach in hippocampal slice cultures to investigate properties of structural plasticity and their modulation by signaling pathways. We found that basal spine turnover was significantly reduced in Fmr1-KO mice, but markedly enhanced by activity. Additionally, activity-mediated spine stabilization was lost in Fmr1-KO mice. Application of the metabotropic glutamate receptor antagonist α-Methyl-4-carboxyphenylglycine (MCPG) enhanced basal turnover, improved spine stability, but failed to reinstate activity-mediated spine stabilization. In contrast, enhancing phosphoinositide-3 kinase (PI3K) signaling, a pathway implicated in various aspects of synaptic plasticity, reversed both basal turnover and activity-mediated spine stabilization. It also restored defective long-term potentiation mechanisms in slices and improved reversal learning in Fmr1-KO mice. These results suggest that modulation of PI3K signaling could contribute to improve the cognitive deficits associated with FXS.
脆性X综合征（FXS）的特征为智力障碍和自闭症特质，是由编码一种参与突触处蛋白质合成调节的蛋白质的FMR1基因沉默所致。据推测，功能性脆性X智力低下蛋白的缺乏会导致突触代谢型谷氨酸受体过度信号传导，进而导致突触成熟和可塑性改变。然而，目前尚不清楚在Fmr基因敲除（Fmr1-KO）小鼠中，活动依赖性脊柱动力学机制是如何受到影响的，以及这些机制是否可以逆转。在此，我们采用重复成像方法对海马切片培养物进行研究，以探究结构可塑性的特性及其信号通路的调节作用。我们发现，Fmr1-KO小鼠的基础脊柱更新显著减少，但活动可使其明显增强。此外，Fmr1-KO小鼠丧失了活动介导的脊柱稳定作用。应用代谢型谷氨酸受体拮抗剂α-甲基-4-羧基苯甘氨酸（MCPG）可增强基础更新，改善脊柱稳定性，但未能恢复活动介导的脊柱稳定作用。相反，增强磷脂酰肌醇-3激酶（PI3K）信号传导（这是一条涉及突触可塑性多个方面的信号通路）可逆转基础更新和活动介导的脊柱稳定作用。它还恢复了切片中存在缺陷的长时程增强机制，并改善了Fmr1-KO小鼠的逆向学习能力。这些结果表明，调节PI3K信号传导可能有助于改善与FXS相关的认知缺陷。
