Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1
Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1
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DOI：
10.1016/j.biopsych.2015.08.028
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发表时间：
2016-08-15
影响因子：
10.6
通讯作者：
Pizzorusso, Tommaso
中科院分区：
文献类型：
--
作者：
Della Sala, Grazia;Putignano, Elena;Pizzorusso, Tommaso
背景：CDKL 5（细胞周期蛋白依赖性激酶样5）在许多严重的神经发育障碍中发生突变，包括非典型Rett综合征。CDKL 5被证明与突触蛋白相互作用，但在体内分析的CDKL 5在树突棘动力学和突触的分子organization的作用仍然lacked.METHODS：在体内双光子显微镜的Cdkl 5（-/y）小鼠的躯体感觉皮层的树突棘的结构动力学监测。突触的功能和可塑性进行了测量，使用电生理记录的兴奋性突触后电流和长时程增强的脑切片和评估突触后密度蛋白95（PSD-95）的表达。最后，我们研究了胰岛素样生长因子1（IGF-1）治疗对CDKL 5 null小鼠恢复突触deficiency.Results：成年突变小鼠表现出显着减少的脊椎密度和PSD-95阳性突触斑点，减少持续的脊椎，受损的长时程增强。在青少年突变体，短期脊柱消除，但不是形成，显着增加。IGF-1的外源性给药挽救了有缺陷的rpS 6磷酸化、棘密度和PSD-95表达。内源性皮质IGF-1水平不受CDKL 5 deletions.CONCLUSIONS：这些数据表明，树突棘的稳定性是强烈调节CDKL 5。此外，我们的数据表明，IGF-1治疗可能是CDKL 5患者临床试验的一个有希望的候选者。
BACKGROUND: CDKL5 (cyclin-dependent kinase-like 5) is mutated in many severe neurodevelopmental disorders, including atypical Rett syndrome. CDKL5 was shown to interact with synaptic proteins, but an in vivo analysis of the role of CDKL5 in dendritic spine dynamics and synaptic molecular organization is still lacking.METHODS: In vivo two-photon microscopy of the somatosensory cortex of Cdkl5(-/y) mice was applied to monitor structural dynamics of dendritic spines. Synaptic function and plasticity were measured using electrophysiological recordings of excitatory postsynaptic currents and long-term potentiation in brain slices and assessing the expression of synaptic postsynaptic density protein 95 (PSD-95). Finally, we studied the impact of insulin-like growth factor 1 (IGF-1) treatment on CDKL5 null mice to restore the synaptic deficits.RESULTS: Adult mutant mice showed a significant reduction in spine density and PSD-95-positive synaptic puncta, a reduction of persistent spines, and impaired long-term potentiation. In juvenile mutants, short-term spine elimination, but not formation, was dramatically increased. Exogenous administration of IGF-1 rescued defective rpS6 phosphorylation, spine density, and PSD-95 expression. Endogenous cortical IGF-1 levels were unaffected by CDKL5 deletion.CONCLUSIONS: These data demonstrate that dendritic spine stabilization is strongly regulated by CDKL5. Moreover, our data suggest that IGF-1 treatment could be a promising candidate for clinical trials in CDKL5 patients.