Johnston T, Duty S
Neurodegenerative Disease Research Group, Wolfson Centre for Age-Related Diseases, Hodgkin Building, King's College London, Guy's Campus, SE1 1UL, London, UK.
Neuroscience. 2003;120(4):1027-35. doi: 10.1016/s0306-4522(03)00418-4.
Loss of striatal dopaminergic innervation in Parkinson's disease (PD) is accompanied by widespread alterations in GABAergic activity within the basal ganglia and thalamus. Accompanying changes in GABA(B) receptor binding have been noted in some basal ganglia regions in parkinsonian primates, suggesting that plasticity of this receptor may also occur in PD. However, the molecular mechanisms underlying the changes in receptor binding and the manner and extent to which different GABA(B) receptor mRNA subunits and splice-variants are affected remain unknown. This study used in situ hybridisation to examine the full profile of changes in expression of the known rat GABA(B) receptor genes and gene variants in the basal ganglia and thalamus of rats, brought about by degeneration of the nigrostriatal tract. All of the GABA(B) mRNA species examined showed unique expression patterns throughout the basal ganglia and thalamus. In addition, all exhibited a marked loss of expression (between 46 and 80%) in the substantia nigra pars compacta of animals bearing a complete 6-hydroxydopamine-induced lesion of the nigrostriatal tract, confirming the presence of these variants in dopaminergic neurones in this region. Further analysis of autoradioagrams revealed additional changes only in GABA(B(1a)) mRNA in discrete anatomical regions. Expression of the GABA(B(1a)) variant was significantly increased in the substantia nigra pars reticulata (33+/-2%), entopeduncular nucleus (26+/-1%) and the subthalamic nucleus (16+/-1%). Since these regions all receive reduced GABAergic innervation following nigrostriatal tract lesioning, it is possible that the increased expression occurs as a compensatory measure. In conclusion, these data demonstrate that GABA(B) receptor genes exhibit regional- and subunit/variant-specific plasticity at the molecular level under parkinsonian conditions.
帕金森病（PD）中纹状体多巴胺能神经支配的丧失伴随着基底神经节和丘脑内GABA能活性的广泛改变。在帕金森病灵长类动物的一些基底神经节区域已发现GABA(B)受体结合的伴随变化，这表明该受体的可塑性在PD中也可能发生。然而，受体结合变化的分子机制以及不同GABA(B)受体mRNA亚基和剪接变体受影响的方式和程度仍然未知。本研究使用原位杂交来检查已知大鼠GABA(B)受体基因和基因变体在大鼠基底神经节和丘脑内的表达变化全貌，这些变化是由黑质纹状体束变性引起的。所检测的所有GABA(B) mRNA种类在整个基底神经节和丘脑中均显示出独特的表达模式。此外，在黑质纹状体束完全6-羟基多巴胺诱导损伤的动物的黑质致密部中，所有种类均表现出明显的表达丧失（46%至80%），证实这些变体存在于该区域的多巴胺能神经元中。对放射自显影片的进一步分析仅发现离散解剖区域中GABA(B(1a)) mRNA有额外变化。GABA(B(1a))变体在黑质网状部（33±2%）、内苍白球核（26±1%）和丘脑底核（16±1%）中的表达显著增加。由于这些区域在黑质纹状体束损伤后均接受减少的GABA能神经支配，因此表达增加可能是一种补偿措施。总之，这些数据表明，在帕金森病状态下，GABA(B)受体基因在分子水平上表现出区域特异性和亚基/变体特异性可塑性。
