Kopra Jaakko J, Panhelainen Anne, Af Bjerkén Sara, Porokuokka Lauriina L, Varendi Kärt, Olfat Soophie, Montonen Heidi, Piepponen T Petteri, Saarma Mart, Andressoo Jaan-Olle
Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland, and.
Institute of Biotechnology and.
J Neurosci. 2017 Feb 8;37(6):1581-1590. doi: 10.1523/JNEUROSCI.1673-16.2016. Epub 2017 Jan 17.
Midbrain dopamine neuron dysfunction contributes to various psychiatric and neurological diseases, including drug addiction and Parkinson's disease. Because of its well established dopaminotrophic effects, the therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) has been studied extensively in various disorders with disturbed dopamine homeostasis. However, the outcomes from preclinical and clinical studies vary, highlighting a need for a better understanding of the physiological role of GDNF on striatal dopaminergic function. Nevertheless, the current lack of appropriate animal models has limited this understanding. Therefore, we have generated novel mouse models to study conditional deletion in the CNS during embryonic development and reduction of striatal GDNF levels in adult mice via AAV-Cre delivery. We found that both of these mice have reduced amphetamine-induced locomotor response and striatal dopamine efflux. Embryonic GDNF deletion in the CNS did not affect striatal dopamine levels or dopamine release, but dopamine reuptake was increased due to increased levels of both total and synaptic membrane-associated dopamine transporters. Collectively, these results suggest that endogenous GDNF plays an important role in regulating the function of dopamine transporters in the striatum. Delivery of ectopic glial cell line-derived neurotrophic factor (GDNF) promotes the function, plasticity, and survival of midbrain dopaminergic neurons, the dysfunction of which contributes to various neurological and psychiatric diseases. However, how the deletion or reduction of GDNF in the CNS affects the function of dopaminergic neurons has remained unknown. Using conditional knock-out mice, we found that endogenous GDNF affects striatal dopamine homeostasis and regulates amphetamine-induced behaviors by regulating the level and function of dopamine transporters. These data regarding the physiological role of GDNF are relevant in the context of neurological and neurodegenerative diseases that involve changes in dopamine transporter function.
中脑多巴胺神经元功能障碍会导致各种精神和神经疾病，包括药物成瘾和帕金森病。由于其已被充分证实的多巴胺营养作用，胶质细胞系源性神经营养因子（GDNF）在多巴胺稳态紊乱的各种疾病中的治疗潜力已得到广泛研究。然而，临床前和临床研究的结果各不相同，这凸显了更好地了解GDNF对纹状体多巴胺能功能的生理作用的必要性。尽管如此，目前缺乏合适的动物模型限制了这一认识。因此，我们构建了新型小鼠模型，以研究胚胎发育期间中枢神经系统中的条件性缺失以及通过腺相关病毒-Cre递送降低成年小鼠纹状体中的GDNF水平。我们发现这两种小鼠的苯丙胺诱导的运动反应和纹状体多巴胺外流均减少。中枢神经系统中胚胎期GDNF的缺失并不影响纹状体多巴胺水平或多巴胺释放，但由于总多巴胺转运体和突触膜相关多巴胺转运体水平均升高，多巴胺再摄取增加。总体而言，这些结果表明内源性GDNF在调节纹状体中多巴胺转运体的功能方面发挥着重要作用。异位胶质细胞系源性神经营养因子（GDNF）的递送可促进中脑多巴胺能神经元的功能、可塑性和存活，而这些神经元的功能障碍会导致各种神经和精神疾病。然而，中枢神经系统中GDNF的缺失或减少如何影响多巴胺能神经元的功能仍不清楚。使用条件性敲除小鼠，我们发现内源性GDNF通过调节多巴胺转运体的水平和功能来影响纹状体多巴胺稳态并调节苯丙胺诱导的行为。这些关于GDNF生理作用的数据在涉及多巴胺转运体功能变化的神经和神经退行性疾病背景下具有相关性。
