The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic transmission and motor learning in mice
The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic transmission and motor learning in mice
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DOI：
10.1523/jneurosci.21-01-00010.2001
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发表时间：
2001-01-01
影响因子：
5.3
通讯作者：
Brose, N
中科院分区：
文献类型：
--
作者：
Augustin, I;Korte, S;Brose, N
在哺乳动物中，Munc13蛋白由三个蛋白家族组成，主要是脑特异性磷酯受体（Munc13-1/2/3）。Munc13-1是突触前活性区的一个组成部分，在突触前活性区中，Munc13-1是必不可少的突触囊泡启动蛋白。与存在于大鼠和小鼠中枢神经系统的大多数神经元中的Munc13-1不同，Munc13-3几乎只在小脑中表达。munc13 - 3mrna存在于颗粒细胞和浦肯野细胞中，但不存在于胶质细胞中。Munc13-3蛋白定位于小脑分子层突触神经节，但未在浦肯野细胞树突中发现，提示Munc13-3与Munc13-1一样，是平行纤维-浦肯野细胞突触的突触前蛋白。为了研究Munc13-3在小脑生理中的作用，我们制造了Munc13-3缺陷突变小鼠。Munc13-3缺失突变体在平行纤维-浦肯野细胞突触上表现出增加的成对脉冲促进。此外，突变小鼠表现出正常的自发运动活动，但学习复杂运动任务的能力受损。我们的数据表明Munc13-3调节平行纤维-浦肯野细胞突触的突触传递。我们认为Munc13-3与Munc13-1在突触囊泡周期的类似步骤中起作用，尽管效率较低。根据目前的数据和Munc13-1的囊泡启动功能，munc13 -3的丢失可能通过干扰囊泡启动导致平行纤维-浦肯野细胞突触释放概率降低。反过来，这将导致配对脉冲促进的增加，并可能导致观察到的运动学习缺陷。
Munc13 proteins form a family of three, primarily brain-specific phorbol ester receptors (Munc13-1/2/3) in mammals. Munc13-1 is a component of presynaptic active zones in which it acts as an essential synaptic vesicle priming protein. In contrast to Munc13-1, which is present in most neurons throughout the rat and mouse CNS, Munc13-3 is almost exclusively expressed in the cerebellum. Munc13-3 mRNA is present in granule and Purkinje cells but absent from glia cells. Munc13-3 protein is localized to the synaptic neuropil of the cerebellar molecular layer but is not found in Purkinje cell dendrites, suggesting that Munc13-3, like Munc13-1, is a presynaptic protein at parallel fiber-Purkinje cell synapses. To examine the role of Munc13-3 in cerebellar physiology, we generated Munc13-3-deficient mutant mice. Munc13-3 deletion mutants exhibit increased paired-pulse facilitation at parallel fiber-Purkinje cell synapses. In addition, mutant mice display normal spontaneous motor activity but have an impaired ability to learn complex motor tasks. Our data demonstrate that Munc13-3 regulates synaptic transmission at parallel fiber-Purkinje cell synapses. We propose that Munc13-3 acts at a similar step of the synaptic vesicle cycle as does Munc13-1, albeit with less efficiency. In view of the present data and the well established vesicle priming function of Munc13-1, it is likely that Munc13-3-loss leads to a reduction in release probability at parallel fiber-Purkinje cell synapses by interfering with vesicle priming. This, in turn, would lead to increases in paired-pulse facilitation and could contribute to the observed deficit in motor learning.