Downregulation of astroglial glutamate transporter GLT-1 in the lateral habenula is associated with depressive-like behaviors in a rat model of Parkinson's disease

• Published in: Neuropharmacology 2021-09, Vol.196, p.108691-108691, Article 108691
• Main Authors: Lyu, Shuxuan, Guo, Yuan, Zhang, Li, Tang, Guoyi, Li, Ruotong, Yang, Jie, Gao, Shasha, Li, Wenjuan, Liu, Jian
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Astrocytes - metabolism; Depression - metabolism; Disease Models, Animal; Down-Regulation; Excitatory Amino Acid Transporter 2 - antagonists & inhibitors; Excitatory Amino Acid Transporter 2 - metabolism; GLT-1; Glutamic Acid - metabolism; Habenula - metabolism; Lateral habenula; Neuron-glial communication; Oxidopamine - toxicity; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - pathology; Pars Compacta - metabolism; Pars Compacta - pathology; PD-Related depression; Rats; Substantia Nigra - metabolism; Substantia Nigra - pathology; Thalamus - metabolism; Thalamus - pathology; Ventral Tegmental Area - metabolism; Ventral Tegmental Area - pathology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2021.108691

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. •Blockade of LHb GLT-1 induced depressive-like behaviors in sham and SNc lesioned rats.•GLT-1 inhibitor enhanced the firing rate of LHb neurons in both groups of rats.•GLT-1 inhibitor increased LHb glutamate levels in both groups of rats.•The lesioned rats were more sensitive to the GLT-1 blockade compared to sham rats.•Astroglial GLT-1 was down-regulated in the LHb after lesioning the SNc.