Pharmacotherapy with sertraline rescues brain development and behavior in a mouse model of CDKL5 deficiency disorder
Pharmacotherapy with sertraline rescues brain development and behavior in a mouse model of CDKL5 deficiency disorder
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DOI：
10.1016/j.neuropharm.2019.107746
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发表时间：
2020-05-01
影响因子：
4.7
通讯作者：
Ciani, Elisabetta
中科院分区：
文献类型：
--
作者：
Fuchs, Claudia;Gennaccaro, Laura;Ciani, Elisabetta
x -连锁细胞周期蛋白依赖性激酶样5 （CDKL5）基因突变导致严重的神经发育障碍，CDKL5缺乏性障碍（CDD）。CDKL5是正确的大脑发育和功能的基础，但CDD异常神经功能障碍的分子机制尚不完全清楚。在杂合Cdkl5敲除（KO）雌性小鼠中，我们发现海马和皮质5-羟色胺能（5-HT）受体表达失调，表明5-HT神经传递受损导致CDD。我们证明，通过选择性5-羟色胺再摄取抑制剂（SSRI）舍曲林靶向受损的5-羟色胺信号传导，可以拯救杂合Cdkl5 KO雌性小鼠中与cdd相关的神经发育和行为缺陷。特别是，慢性治疗舍曲林正常化运动，刻板印象和自闭症样特征，以及Cdkl5 KO小鼠的空间记忆。这些积极的行为效应伴随着神经元存活、树突发育和突触连通性的恢复。在分子水平上，舍曲林增加脑源性神经营养因子（BDNF）的表达，恢复酪氨酸激酶B （TrkB）及其下游靶细胞外信号调节激酶（ERK1/2）的异常磷酸化水平。由于舍曲林是fda批准的药物，具有广泛的安全性和耐受性数据包，即使对儿童也是如此，我们的研究结果表明舍曲林可能改善CDD儿童的神经发育。这篇文章是题为“血清素研究：跨越尺度和界限”的特刊的一部分。
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a severe neurodevelopmental disorder, CDKL5 deficiency disorder (CDD). CDKL5 is fundamental for correct brain development and function, but the molecular mechanisms underlying aberrant neurologic dysfunction in CDD are incompletely understood. Here we show a dysregulation of hippocampal and cortical serotonergic (5-HT) receptor expression in heterozygous Cdkl5 knockout (KO) female mice, suggesting that impaired 5-HT neurotransmission contributes to CDD. We demonstrate that targeting impaired 5-HT signaling via the selective serotonin reuptake inhibitor (SSRI) sertraline rescues CDD-related neurodevelopmental and behavioral defects in heterozygous Cdkl5 KO female mice. In particular, chronic treatment with sertraline normalized locomotion, stereotypic and autistic-like features, and spatial memory in Cdkl5 KO mice. These positive behavioral effects were accompanied by restored neuronal survival, dendritic development and synaptic connectivity. At a molecular level, sertraline increased brain-derived neurotrophic factor (BDNF) expression and restored abnormal phosphorylation levels of tyrosine kinase B (TrkB) and its downstream target the extracellular signal-regulated kinase (ERK1/2). Since sertraline is an FDA-approved drug with an extensive safety and tolerability data package, even for children, our findings suggest that sertraline may improve neurodevelopment in children with CDD.This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.