Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory.
Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory.
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DOI：
10.1371/journal.pone.0196587
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Tanaka T
中科院分区：
文献类型：
--
作者：
Okuda K;Takao K;Watanabe A;Miyakawa T;Mizuguchi M;Tanaka T
细胞周期蛋白依赖性激酶样5（CDKL 5）基因突变会导致严重的神经发育障碍。最近，我们通过靶向C57 BL/6 N背景上的外显子2产生了Cdkl 5 KO小鼠，并证明了海马中含有GluN 2B的N-甲基-D-天冬氨酸（NMDA）受体的突触后过度积累。在目前的研究中，我们对Cdkl 5 KO小鼠进行了一系列综合行为测试，旨在从运动、情感、社会和认知/记忆功能的整体角度揭示CDKL 5缺失的影响，并确定其未确定的作用。对成年Cdk 15-/Y和+/Y小鼠应用神经学筛选、旋转棒、热板、前脉冲抑制、光/暗转换、旷场、高架十字迷宫、Porsolt强迫游泳、尾部悬吊、单室和三室社交互动、24-h家庭笼监测、情境和线索恐惧条件反射、巴恩斯迷宫和T-迷宫测试。Cdkl 5-/Y小鼠表现出步态的轻度改变。情绪行为分析显示Cdkl 5-/Y小鼠的焦虑样行为显著增强。Cdkl 5-/Y小鼠的抑郁样行为和社会互动发生了独特的改变。Cdkl 5-/Y小鼠的情境和线索恐惧条件反射与对照小鼠相当;然而，Cdkl 5-/Y小鼠在改变的情境中在pretone期间显示出显著增加的冻结时间和显著减少的行进距离。空间参考记忆的获得和长期保持都明显受损。海马CA 1区锥体神经元的形态计量学分析显示受损的树突状分支和不成熟的脊髓发育在Cdkl 5-/Y小鼠。这些结果表明，CDKL 5在调节情绪行为，特别是焦虑和恐惧相关的反应，并在获得和长期保留的空间参考记忆，这表明，重点和特别注意这些赤字在CDKL 5缺乏症的具体机制。
Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three-chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 -/Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder.
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