The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression.
The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression.
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DOI：
10.1523/jneurosci.3080-06.2006
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发表时间：
2006-11-29
影响因子：
5.3
通讯作者：
Dolphin, Annette C
中科院分区：
文献类型：
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作者：
Donato, Roberta;Page, Karen M;Koch, Dietlind;Nieto-Rostro, Manuela;Foucault, Isabelle;Davies, Anthony;Wilkinson, Tonia;Rees, Michele;Edwards, Frances A;Dolphin, Annette C
小鼠突变体ducky及其等位基因ducky 2 J代表了以棘波癫痫发作和小脑共济失调为特征的失神癫痫模型。这些小鼠在编码α2δ-2钙通道亚基的Cacna 2d 2中具有突变。与共济失调表型相关，α2δ-2 mRNA在小脑浦肯野细胞（PC）中强烈表达。Cacna 2d 2du 2 J突变导致编码区两个碱基对缺失和α2δ-2蛋白的完全丢失。在这里，我们发现du 2 J/du 2 J小鼠的体细胞钙电流减少了30%，并且在22°C下自发PC放电率显著下降，伴随着放电规律性的降低，这不受阻断突触输入到PC的影响。在34°C下，du 2 J/du 2 J PC不显示自发的内在活性。Du 2 J/du 2 J小鼠的小脑中也有几个与PC功能相关的基因表达的改变。在P21，酪氨酸羟化酶mRNA升高，腱生蛋白-C基因表达降低。尽管du 2 J/+小鼠的α2δ-2蛋白显著降低，但它们未显示PC体细胞钙电流下降或小脑酪氨酸羟化酶基因表达增加。然而，du 2 J/+ PC确实表现出与α2δ-2的降低相关的放电率的显著降低。未来研究的一个假设是，对基因表达的影响是由于体细胞钙电流减少而发生的，而对PC放电的影响是由于α2δ-2丢失和/或索马以外区域的钙电流和钙依赖性过程减少而发生的长期结果。
The mouse mutant ducky and its allele ducky2J represent a model for absence epilepsy characterized by spike-wave seizures, and cerebellar ataxia. These mice have mutations in Cacna2d2, which encodes the α2δ-2 calcium channel subunit. Of relevance to the ataxic phenotype, α2δ-2 mRNA is strongly expressed in cerebellar Purkinje cells (PCs). The Cacna2d2du2J mutation results in a two base-pair deletion in the coding region and a complete loss of α2δ-2 protein. Here we show that du2J/du2J mice have a 30% reduction in somatic calcium current, and a marked fall in the spontaneous PC firing rate at 22°C, accompanied by a decrease in firing regularity, which is not affected by blocking synaptic input to PCs. At 34°C du2J/du2J PCs show no spontaneous intrinsic activity. Du2J/du2J mice also have alterations in the cerebellar expression of several genes related to PC function. At P21 there is an elevation of tyrosine hydroxylase mRNA and a reduction in tenascin-C gene expression. Although du2J/+ mice have a marked reduction in α2δ-2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tryrosine hydroxylase gene expression. However, du2J/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in α2δ-2. A hypothesis for future study is that effects on gene expression occur as a result of a reduction in somatic calcium currents, whereas effects on PC firing occur as a long-term result of loss of α2δ-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.