Abnormalities in synaptic dynamics during development in a mouse model of spinocerebellar ataxia type 1.
Abnormalities in synaptic dynamics during development in a mouse model of spinocerebellar ataxia type 1.
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DOI：
10.1038/srep16102
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发表时间：
2015-11-04
影响因子：
4.6
通讯作者：
Nagai Y
中科院分区：
文献类型：
--
作者：
Hatanaka Y;Watase K;Wada K;Nagai Y
迟发性神经退行性疾病的特征在于神经系统症状和进行性神经元死亡。越来越多的证据表明，神经元功能障碍，而不是神经元死亡，导致神经退行性疾病的症状。然而，在细胞死亡之前发生的功能障碍的潜在机制仍然不清楚。为了研究这种功能障碍的突触基础，我们采用体内双光子成像来分析兴奋性突触后树枝状突起。我们使用Sca 1154 Q/2 Q小鼠，这是一种已建立的多聚谷氨酰胺疾病脊髓小脑共济失调1型（SCA 1）基因敲入小鼠模型，该模型复制了人类SCA 1的特征，包括共济失调、认知障碍和神经元死亡。我们发现，Sca 1154 Q/2 Q小鼠表现出更大的突触不稳定性比对照组，没有突触损失，在大脑皮层，没有观察到明显的神经元死亡，甚至在发病前的明显症状。有趣的是，这种异常的突触不稳定性在Sca 1154 Q/2 Q小鼠中从突触发育阶段就很明显，并持续到成年期。在突触成熟前，Sca 1154 Q/2 Q小鼠的突触支架蛋白的表达也低于对照组。随着症状的进展，突触丢失变得明显。这些结果表明，异常的突触不稳定性，伴随着在突触发育过程中支架蛋白的表达减少，是一个非常早期的病理学，在SCA 1的不同的神经症状和神经元细胞死亡之前。
Late-onset neurodegenerative diseases are characterized by neurological symptoms and progressive neuronal death. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, causes the symptoms of neurodegenerative diseases. However, the mechanisms underlying the dysfunction that occurs prior to cell death remain unclear. To investigate the synaptic basis of this dysfunction, we employed in vivo two-photon imaging to analyse excitatory postsynaptic dendritic protrusions. We used Sca1154Q/2Q mice, an established knock-in mouse model of the polyglutamine disease spinocerebellar ataxia type 1 (SCA1), which replicates human SCA1 features including ataxia, cognitive impairment, and neuronal death. We found that Sca1154Q/2Q mice exhibited greater synaptic instability than controls, without synaptic loss, in the cerebral cortex, where obvious neuronal death is not observed, even before the onset of distinct symptoms. Interestingly, this abnormal synaptic instability was evident in Sca1154Q/2Q mice from the synaptic developmental stage, and persisted into adulthood. Expression of synaptic scaffolding proteins was also lower in Sca1154Q/2Q mice than controls before synaptic maturation. As symptoms progressed, synaptic loss became evident. These results indicate that aberrant synaptic instability, accompanied by decreased expression of scaffolding proteins during synaptic development, is a very early pathology that precedes distinct neurological symptoms and neuronal cell death in SCA1.