Institute of Neuroanatomy, Hannover Medical School, Hannover, Germany.
Neurobiol Dis. 2013 Nov;59:230-43. doi: 10.1016/j.nbd.2013.07.016. Epub 2013 Aug 11.
Dopamine (DA) depletion in the nigrostriatal system leads to basal ganglia dysfunction both in Parkinson's disease (PD) and in 6-hydroxy dopamine (6-OHDA)-lesioned rats with neuronal hyperactivity in the subthalamic nucleus (STN), i.e. increased firing rate and burst activity, together with enhanced beta oscillatory activity. Moreover, intrastriatal transplantation of DA neurons has been shown to functionally re-innervate the host striatum and restore DA input. However, the effects of those transplanted cells on the STN are not well characterized. Therefore, we transplanted cells, derived from the ventral mesencephalon of E12 rat embryos, intrastriatally in the unilateral 6-OHDA-lesioned rat model of PD. We combined behavioral and histological findings with electrophysiological extracellular recordings in the STN, as well as qRT-PCR analyses of dopaminergic, GABAergic, and glutamatergic transporter and receptor genes in the striatum and the STN. Transplanted animals displayed improved rotational behavior after amphetamine injection by 50% in rats with small grafts (586±109 SEM dopamine cells), or even overcompensation by 116% in rats with large grafts (3486±548 SEM dopamine cells). Electrophysiological measurements revealed, that in rats with large grafts burst activity was not affected, while STN neuronal firing rate, as well as beta oscillatory activity was alleviated, whereas small grafts had less impact. Interestingly, both behavioral and electrophysiological measures were dependent on the number of surviving tyrosine hydroxylase positive cells. Although grafted rats displayed restored expression of the GABA synthesizing enzymes Gad65 and Gad67 in the striatum compared to naive rats, the grafts induced a decreased mRNA expression of dopamine receptor Drd2, glutamate receptors AMPA3, NMDA2A, and NMDA2B, and glutamate transporter Eaat3. Interestingly, the NMDA receptor subunit 2B and glutamate transporter Eaat3 were also less expressed in the STN of grafted animals compared to naive rats. In summary, DA grafts restore functional deficits and cause partial improvement of subthalamic neuronal activity. Incomplete recovery, however, may be due to decreased receptor gene expression induced by DA grafts in the striatum and in the STN.
纹状体系统中的多巴胺（DA）耗竭会导致基底节功能障碍，既存在于帕金森病（PD）患者中，也存在于 6-羟多巴胺（6-OHDA）损伤的大鼠中，其中丘脑下核（STN）神经元过度活跃，即发射率和爆发活动增加，同时β振荡活动增强。此外，已经证明纹状体内移植 DA 神经元可以功能性地重新支配宿主纹状体并恢复 DA 输入。然而，那些移植细胞对 STN 的影响还没有很好地表征。因此，我们将源自 E12 大鼠胚胎腹侧中脑的细胞移植到单侧 6-OHDA 损伤的 PD 大鼠模型的纹状体中。我们将行为和组织学发现与 STN 的电生理细胞外记录以及纹状体和 STN 中的多巴胺能、GABA 能和谷氨酸能转运体和受体基因的 qRT-PCR 分析相结合。移植动物在接受安非他命注射后，其旋转行为得到改善，小移植物（586±109 SEM 多巴胺细胞）的改善率为 50%，大移植物（3486±548 SEM 多巴胺细胞）的改善率甚至超过 116%。电生理测量显示，在大移植物中，爆发活动没有受到影响，而 STN 神经元发射率以及β振荡活动则得到缓解，而小移植物的影响较小。有趣的是，行为和电生理测量都依赖于存活的酪氨酸羟化酶阳性细胞的数量。尽管移植大鼠与未处理大鼠相比，在纹状体中表现出 GABA 合成酶 Gad65 和 Gad67 的表达恢复，但移植诱导了多巴胺受体 Drd2、AMPA3、NMDA2A 和 NMDA2B 谷氨酸受体和谷氨酸转运体 Eaat3 的 mRNA 表达降低。有趣的是，与未处理大鼠相比，移植动物的 STN 中 NMDA 受体亚基 2B 和谷氨酸转运体 Eaat3 的表达也较低。总之，DA 移植恢复了功能缺陷，并导致 STN 神经元活动的部分改善。然而，不完全恢复可能是由于 DA 移植在纹状体和 STN 中诱导的受体基因表达降低所致。
