Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
Department of Rehabilitation Medicine, The Second Hospital, Xi'an Jiaotong University, Xi'an, 710004, China.
Neuropharmacology. 2021 Sep 15;196:108691. doi: 10.1016/j.neuropharm.2021.108691. Epub 2021 Jun 28.
Recent studies show that neuron-glial communication plays an important role in neurological diseases. Particularly, dysfunction of astroglial glutamate transporter GLT-1 has been involved in various neuropsychiatric disorders, including Parkinson's disease (PD) and depression. Our previous studies indicated hyperactivity of neurons in the lateral habenula (LHb) of hemiparkinsonian rats with depressive-like behaviors. Thus, we hypothesized that impaired expression or function of GLT-1 in the LHb might be a potential contributor to LHb hyperactivity, which consequently induces PD-related depression. In the study, unilateral lesions of the substantia nigra pars compacta (SNc) by 6-hydroxydopamine in rats induced depressive-like behaviors and resulted in neuronal hyperactivity as well as increased glutamate levels in the LHb compared to sham-lesioned rats. Intra-LHb injection of GLT-1 inhibitor WAY-213613 induced the depressive-like behaviors in both groups, but the dose producing behavioral effects in the lesioned rats was lower than that of sham-lesioned rats. In the two groups of rats, WAY-213613 increased the firing rate of LHb neurons and extracellular levels of glutamate, and these excitatory effects in the lesioned rats lasted longer than those in sham-lesioned rats. The functional changes of the GLT-1 which primarily expresses in astrocytes in the LHb may attribute to its downregulation after degeneration of the nigrostriatal pathway. Bioinformatics analysis showed that GLT-1 is correlated with various biomarkers of PD and depression risks. Collectively, our study suggests that astroglial GLT-1 in the LHb regulates the firing activity of the neurons, whereupon its downregulation and dysfunction are closely associated with PD-related depression.
最近的研究表明，神经元-胶质细胞通讯在神经疾病中起着重要作用。特别是，星形胶质细胞谷氨酸转运体 GLT-1 的功能障碍与各种神经精神疾病有关，包括帕金森病（PD）和抑郁症。我们之前的研究表明，具有抑郁样行为的半帕金森病大鼠外侧缰核（LHb）中的神经元过度活跃。因此，我们假设 LHb 中 GLT-1 的表达或功能受损可能是 LHb 过度活跃的潜在原因，进而导致与 PD 相关的抑郁。在这项研究中，6-羟多巴胺单侧损毁大鼠黑质致密部（SNc）诱导出抑郁样行为，并导致 LHb 中神经元过度活跃以及谷氨酸水平升高，与假手术组大鼠相比。LHb 内注射 GLT-1 抑制剂 WAY-213613 可在两组大鼠中诱导出抑郁样行为，但在损伤组大鼠中产生行为效应的剂量低于假手术组大鼠。在两组大鼠中，WAY-213613 增加了 LHb 神经元的放电率和细胞外谷氨酸水平，并且损伤组大鼠的这些兴奋作用持续时间长于假手术组大鼠。主要在星形胶质细胞中表达的 GLT-1 在 LHb 中的功能变化可能归因于黑质纹状体通路退化后的下调。生物信息学分析显示，GLT-1 与 PD 和抑郁风险的各种生物标志物相关。总之，我们的研究表明，LHb 中的星形胶质细胞 GLT-1 调节神经元的放电活动，其下调和功能障碍与与 PD 相关的抑郁密切相关。
