Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305.
Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10235-E10244. doi: 10.1073/pnas.1811086115. Epub 2018 Oct 4.
Cerebellins are important neurexin ligands that remain incompletely understood. Two critical questions in particular remain unanswered: do different cerebellins perform distinct functions, and do these functions act in the initial establishment of synapses or in rendering nascent synapses capable of normal synaptic transmission? Here we show that in mice, Cbln2 and Cbln4 are expressed in the medial habenula (MHb) nucleus in different types of neurons that project to distinct target neurons in the interpeduncular nucleus. Conditional genetic deletion of Cbln2 in the MHb impaired synaptic transmission at Cbln2 synapses in the interpeduncular neurons within 3 wk, but decreased synapse numbers only after 3 mo, suggesting a functional, but not a structural, requirement for Cbln2 in synapses formed by Cbln2-expressing neurons. In contrast, genetic deletions of Cbln4 in the MHb had no major effect on synaptic transmission or synapse numbers in interpeduncular target neurons. Nevertheless, MHb ablation of both Cbln2 and Cbln4 significantly impaired behavioral responses in mice, but affected different types of behaviors. Specifically, Cbln2 MHb deletions decreased spatial learning, as measured in the water T-maze, whereas Cbln4 MHb deletions increased anxiety levels, as monitored in the open field test and elevated plus maze. Thus, Cbln2 and Cbln4 are expressed in distinct MHb neurons that contribute to different behaviors.
小脑肽是重要的神经连接蛋白配体，但它们的功能仍不完全清楚。有两个关键问题尚未得到解答：不同的小脑肽是否具有不同的功能，以及这些功能是在突触的初始形成中发挥作用，还是使新生突触能够进行正常的突触传递？在这里，我们发现在小鼠中，Cbln2 和 Cbln4 在投射到中脑脚间核中不同靶神经元的中脑缰核神经元中表达。在缰核中条件性敲除 Cbln2 会在 3 周内损害中脑脚间核神经元中 Cbln2 突触的传递，但只有在 3 个月后才会减少突触数量，这表明 Cbln2 在由 Cbln2 表达神经元形成的突触中具有功能而非结构要求。相比之下，在缰核中敲除 Cbln4 对中脑脚间核靶神经元的突触传递或突触数量没有重大影响。然而，缰核中 Cbln2 和 Cbln4 的双重缺失显著损害了小鼠的行为反应，但影响了不同类型的行为。具体而言，缰核中 Cbln2 的缺失降低了小鼠在水 T 迷宫中的空间学习能力，而缰核中 Cbln4 的缺失增加了焦虑水平，这可以通过旷场试验和高架十字迷宫试验监测到。因此，Cbln2 和 Cbln4 在不同的缰核神经元中表达，这些神经元对不同的行为有贡献。
