Full-length RIM1 and 2 are key components of the presynaptic active zone that ubiquitously control excitatory and inhibitory neurotransmitter release. Here, we report that the function of the small RIM isoform RIM4, consisting of a single C2 domain, is strikingly different from that of the long isoforms. RIM4 is dispensable for neurotransmitter release but plays a postsynaptic, cell-type specific role in cerebellar Purkinje cells that is essential for normal motor function. In the absence of RIM4, Purkinje cell intrinsic firing is reduced and caffeine-sensitive, and dendritic integration of climbing fibre input is disturbed. Mice lacking RIM4, but not mice lacking RIM1/2, selectively in Purkinje cells exhibit a severe, hours-long paroxysmal dystonia. These episodes can also be induced by caffeine, ethanol or stress and closely resemble the deficits seen with mutations of the PNKD (paroxysmal non-kinesigenic dystonia) gene. Our data reveal essential postsynaptic functions of RIM proteins and show non-overlapping specialized functions of a small isoform despite high homology to a single domain in the full-length proteins.

中文翻译：

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阵发性肌张力障碍是由浦肯野细胞中 RIM4 缺失引起的

全长 RIM1 和 2 是突触前活性区的关键组成部分，普遍控制兴奋性和抑制性神经递质的释放。在这里，我们报道了由单个 C2 结构域组成的小 RIM 异构体 RIM4 的功能与长异构体的功能显着不同。RIM4 对于神经递质释放来说是可有可无的，但在小脑浦肯野细胞中发挥突触后细胞类型特异性作用，这对于正常运动功能至关重要。在缺乏 RIM4 的情况下，浦肯野细胞内在放电会减少并且对咖啡因敏感，并且攀爬纤维输入的树突整合会受到干扰。缺乏 RIM4 的小鼠，但缺乏 RIM1/2 的小鼠，在浦肯野细胞中选择性地表现出严重的、长达数小时的阵发性肌张力障碍。这些发作也可由咖啡因、乙醇或压力引起，并且与 PNKD（阵发性非运动性肌张力障碍）基因突变所见的缺陷非常相似。我们的数据揭示了 RIM 蛋白的重要突触后功能，并显示了小亚型的非重叠专门功能，尽管与全长蛋白中的单个结构域具有高度同源性。