Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model
Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model
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DOI：
10.1172/jci83541
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发表时间：
2015-11-01
影响因子：
15.9
通讯作者：
Elgersma, Ype
中科院分区：
文献类型：
--
作者：
Bruinsma, Caroline F.;Schonewille, Martijn;Elgersma, Ype
Angelman综合征（AS）是一种严重的神经系统疾病，其与显著的运动和平衡障碍相关，这些障碍被广泛认为是由于小脑起源的缺陷。在这里，使用小脑特异性前庭眼反射（VOR）范例，我们确定小脑功能仅轻度受损的Ube 3a（m-/P+）小鼠模型的AS。VOR相逆转学习在这些动物中是奇异受损的，并与高尔基体细胞和颗粒细胞之间的紧张性抑制减少相关。浦肯野细胞生理学，相反，是正常的AS小鼠所示的突触可塑性和自发放电特性，类似于那些控制。因此，在浦肯野细胞中选择性缺失Ube 3a后，VOR相位逆转学习和运动均未受损。然而，尽管未能改善AS小鼠的小脑学习，但α CaMK II抑制性磷酸化的遗传正常化完全挽救了运动缺陷，这表明运动学习中的小脑外回路参与。我们通过小脑特异性恢复Ube 3a证实了这一假设，Ube 3a改善了小脑的学习缺陷，但没有挽救运动缺陷。这种运动和小脑表型的双重分离强烈表明AS小鼠的运动缺陷并不源于小脑皮质功能受损。我们的研究结果提供了重要的见解与AS相关的运动缺陷的病因。
Angelman syndrome (AS) is a severe neurological disorder that is associated with prominent movement and balance impairments that are widely considered to be due to defects of cerebellar origin. Here, using the cerebellar-specific vestibulo-ocular reflex (VOR) paradigm, we determined that cerebellar function is only mildly impaired in the Ube3a(m-/P+) mouse model of AS. VOR phase-reversal learning was singularly impaired in these animals and correlated with reduced tonic inhibition between Golgi cells and granule cells. Purkinje cell physiology, in contrast, was normal in AS mice as shown by synaptic plasticity and spontaneous firing properties that resembled those of controls. Accordingly, neither VOR phas-ereversal learning nor locomotion was impaired following selective deletion of Ube3a in Purkinje cells. However, genetic normalization of alpha CaMKII inhibitory phosphorylation fully rescued locomotor deficits despite failing to improve cerebellar learning in AS mice, suggesting extracerebellar circuit involvement in locomotor learning. We confirmed this hypothesis through cerebellum-specific reinstatement of Ube3a, which ameliorated cerebellar learning deficits but did not rescue locomotor deficits. This double dissociation of locomotion and cerebellar phenotypes strongly suggests that the locomotor deficits of AS mice do not arise from impaired cerebellar cortex function. Our results provide important insights into the etiology of the motor deficits associated with AS.