Roles of Cbln1 in Non-Motor Functions of Mice
Roles of Cbln1 in Non-Motor Functions of Mice
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DOI：
10.1523/jneurosci.0322-16.2016
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发表时间：
2016-11-16
影响因子：
5.3
通讯作者：
Yuzaki, Michisuke
中科院分区：
文献类型：
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作者：
Otsuka, Shintaro;Konno, Kohtarou;Yuzaki, Michisuke
小脑被认为除了在人类的运动协调和运动学习中发挥作用之外，还参与认知功能。小脑蛋白1（Cbln 1）主要表达于小脑颗粒细胞中，在平行纤维-浦肯野细胞突触的形成和功能中起关键作用。尽管编码Cbln 1及其突触后受体（delta 2谷氨酸受体（GluD 2））的基因被认为与自闭症样特征和许多精神疾病有关，但这种认知障碍是否由小脑功能障碍引起仍不清楚。在本研究中，我们研究了Cbln 1信号是否以及如何参与成年小鼠的非运动功能。我们发现，收购和保留/检索线索和上下文的恐惧记忆Cbln 1基因敲除小鼠受损。原位杂交和免疫组织化学分析表明，Cbln 1表达在各种小脑外区域，包括压后颗粒皮质和海马。在海马中，Cbln 1免疫反应性存在于齿状回的分子层和腔隙分子层，而没有明显的mRNA表达，表明Cbln 1是由穿通通路纤维提供的。保留/检索，但不收购，线索和上下文的恐惧记忆受损的前脑占主导地位的Cbln 1基因敲除小鼠。在径向臂水迷宫中的空间学习也被废除。相反，在小脑占主导地位的Cbln 1基因敲除小鼠中，恐惧记忆的获得受到影响。这些结果表明，Cbln 1在前脑和小脑介导的特定方面的恐惧条件反射和空间记忆的差异和Cbln 1信号可能调节运动和非运动功能在多个大脑区域。
The cerebellum is thought to be involved in cognitive functions in addition to its well established role in motor coordination and motor learning in humans. Cerebellin 1 (Cbln1) is predominantly expressed in cerebellar granule cells and plays a crucial role in the formation and function of parallel fiber-Purkinje cell synapses. Although genes encoding Cbln1 and its postsynaptic receptor, the delta2 glutamate receptor (GluD2), are suggested to be associated with autistic-like traits and many psychiatric disorders, whether such cognitive impairments are caused by cerebellar dysfunction remains unclear. In the present study, we investigated whether and how Cbln1 signaling is involved in non-motor functions in adult mice. We show that acquisition and retention/retrieval of cued and contextual fear memory were impaired in Cbln1-null mice. In situ hybridization and immunohistochemical analyses revealed that Cbln1 is expressed in various extracerebellar regions, including the retrosplenial granular cortex and the hippocampus. In the hippocampus, Cbln1 immunoreactivity was present at the molecular layer of the dentate gyrus and the stratum lacunosum-moleculare without overt mRNA expression, suggesting that Cbln1 is provided by perforant path fibers. Retention/retrieval, but not acquisition, of cued and contextual fear memory was impaired in forebrain-predominant Cbln1-null mice. Spatial learning in the radial arm water maze was also abrogated. In contrast, acquisition of fear memory was affected in cerebellum-predominant Cbln1-null mice. These results indicate that Cbln1 in the forebrain and cerebellum mediates specific aspects of fear conditioning and spatial memory differentially and that Cbln1 signaling likely regulates motor and non-motor functions in multiple brain regions.