Decreased GAD67 mRNA levels in cerebellar purkinje cells in autism: pathophysiological implications
Decreased GAD67 mRNA levels in cerebellar purkinje cells in autism: pathophysiological implications
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DOI：
10.1007/s00401-006-0176-3
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发表时间：
2007-05-01
影响因子：
12.7
通讯作者：
Blatt, Gene J.
中科院分区：
文献类型：
--
作者：
Yip, Jane;Soghomonian, Jean-Jacques;Blatt, Gene J.
最近在自闭症小脑组织中发现谷氨酸脱羧酶(GAD)65和67亚型的蛋白水平降低，这增加了个体神经元中GABA产生的异常调节可能与自闭症的临床特征有关的可能性。在自闭症中，浦肯野细胞数量的减少被广泛报道。目前尚不清楚浦肯野细胞中是否也发生了转录水平的GAD变化。使用一种新的方法，本研究在成人自闭症患者和对照病例中使用原位杂交技术对浦肯野细胞中含量最丰富的GAD67mRNA进行了定量。结果表明，自闭症组GAD67mRNA水平降低了40%(P<；0.0001；双尾t检验)，这表明浦肯野细胞向小脑核团的GABA输入减少，潜在地扰乱了小脑向高级关联皮质的输出，影响运动和/或认知功能。这些发现也可能有助于理解先前关于边缘和大脑皮质区域GABA能系统改变的报道，这些改变导致自闭症大脑中更广泛的病理生理学。
The recent identification of decreased protein levels of glutamate decarboxylase (GAD) 65 and 67 isoforms in the autistic cerebellar tissue raises the possibility that abnormal regulation of GABA production in individual neurons may contribute to the clinical features of autism. Reductions in Purkinje cell number have been widely reported in autism. It is not known whether the GAD changes also occur in Purkinje cells at the level of transcription. Using a novel approach, the present study quantified GAD67 mRNA, the most abundant isoform in Purkinje cells, using in situ hybridization in adult autistic and control cases. The results indicate that GAD67 mRNA level was reduced by 40% in the autistic group (P < 0.0001; two-tailed t test), suggesting that reduced Purkinje cell GABA input to the cerebellar nuclei potentially disrupts cerebellar output to higher association cortices affecting motor and/or cognitive function. These findings may also contribute to the understanding of previous reports of alterations in the GABAergic system in limbic and cerebro-cortical areas contributing to a more widespread pathophysiology in autistic brains.