GLT-1 is the major glutamate transporter in the brain, and is expressed in astrocytes and in axon terminals in the hippocampus, cortex, and striatum. Neuronal GLT-1 accounts for only 5-10% of total brain GLT-1 protein, and its function is uncertain. In HD, synaptic dysfunction of the corticostriate synapse is well-established. Transcriptional dysregulation is a key feature of HD. We hypothesized that deletion of neuronal GLT-1, because it is expressed in axon terminals in the striatum, might produce a synaptopathy similar to that present in HD. If true, then some of the gene expression changes observed in HD might also be observed in the neuronal GLT-1 knockout. In situ hybridization using 33P labeled oligonucleotide probes was carried out to assess localization and expression of a panel of genes known to be altered in expression in HD. We found changes in the expression of cannabinoid receptors 1 and 2, preproenkaphalin, and PDE10A in the striatum of mice in which the GLT-1 gene was inactivated in neurons by expression of synapsin-Cre, compared to wild-type littermates. These changes in expression were observed at 12 weeks of age but not at 6 weeks of age. No changes in DARPP-32, PDE1B, NGFIA, or β-actin expression were observed. In addition, we found widespread alteration in expression of the dynamin 1 gene. The changes in expression in the neuronal GLT-1 knockout of genes thought to exemplify HD transcriptional dysregulation suggest an overlap in the synaptopathy caused by neuronal GLT-1 deletion and HD. These data further suggest that specific changes in expression of cannabinoid receptors, preproenkephalin, and PDE10A, considered to be the hallmark of HD transcriptional dysregulation, may be produced by an abnormality of glutamate homeostasis under the regulation of neuronal GLT-1, or a synaptic disturbance caused by that abnormality, independently of mutation in huntingtin.

中文翻译：

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在缺少突变亨廷顿蛋白的情况下，亨廷顿舞蹈病的转录失调模式是由神经元GLT-1的敲除产生的。

GLT-1是大脑中主要的谷氨酸转运蛋白，在星形胶质细胞和海马，皮层和纹状体的轴突末端表达。神经元GLT-1仅占大脑总GLT-1蛋白的5-10％，其功能尚不确定。在HD中，皮质三突触的突触功能障碍是公认的。转录失调是HD的关键特征。我们假设神经元GLT-1的缺失，因为它在纹状体的轴突末端表达，可能会产生类似于HD的突触病。如果为真，那么在神经元GLT-1基因敲除中也可能观察到HD中观察到的某些基因表达变化。使用33P标记的寡核苷酸探针进行了原位杂交，以评估一组已知在HD中表达发生改变的基因的定位和表达。我们发现与野生型同窝仔相比，通过突触素-Cre的表达使神经元中的GLT-1基因失活的小鼠纹状体中大麻素受体1和2，前原脑啡肽和PDE10A的表达发生了变化。在12周龄时观察到这些表达变化，但在6周龄时未观察到。没有观察到DARPP-32，PDE1B，NGFIA或β-肌动蛋白表达的变化。此外，我们发现了dynamin 1基因表达的广泛变化。人们认为神经元GLT-1基因敲除的基因表达变化代表HD转录失调，提示神经元GLT-1缺失和HD引起的突触病重叠。这些数据进一步表明，大麻素受体，前脑啡肽和PDE10A的表达发生了特定变化，