Abstract
Astrocytes contribute to pathogenesis of neuropsychiatric disorders, including major depression. Stimulation of astroglial 5-HT2B receptors transactivates epidermal growth factor receptors (EGFRs) and regulates gene expression. Previously we reported that expression of 5-HT2B receptors in cortical astrocytes is down-regulated in animals, which developed anhedonia in response to chronic stress; moreover this down-regulation as well as anhedonia, are reversed by chronic treatment with fluoxetine. In this study we have investigated whether astrocytic 5-HT2B receptor is involved in anhedonia in C57BL/6 mice model of Parkinson’ disease (PD) induced by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 days. The MPTP treatment induced anhendonia in 66.7% of animals. The appearance of depressive behavior was accompanied with motor deficiency and decrease of tyrosine hydroxylase (TH) expression. Expression of mRNA and protein of 5-HT2B receptor in animals that became anhedonic decreased to 77.3 and 79.3% of control groups, respectively; in animals that received MPTP but did not develop anhedonia the expression of 5-HT2B receptor did not change. Experiments with FACS-sorted isolated cells demonstrated that decrease in 5-HT2B receptor expression was confined to astrocytes, and did not occur in neurons. Fluoxetine corrected MPTP-induced decrease of 5-HT2B receptor expression and depressive behavior. Our findings indicate that regulation of gene expression of 5-HT2B receptors in astroglia may be associated with pathophysiological evolution of PD-induced depression.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder originating from a progressive loss of dopamine-containing neurons in the substantia nigra pars compacta (SNpc; Hornykiewicz and Kish, 1987)
Similar results were obtained in three independent experiments
To the best of our knowledge, our present work is the first that suggests the role of astroglial 5-HT2B receptors in the pathophysiology of depression associated with MPTP model of PD
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder originating from a progressive loss of dopamine-containing neurons in the substantia nigra pars compacta (SNpc; Hornykiewicz and Kish, 1987). The morbid changes associated with depression affect neurons; there is constantly increasing evidence that astrocytes contribute to pathogenesis of various neuropsychiatric disorders (Verkhratsky et al, 2014). The number of astrocytes is significantly decreased in the brain of depressed patients (McNally et al, 2008), whereas treatment with antidepressants has been shown to increase expression of astrocytic markers glial fibrillary acidic protein (GFAP) and ALDH1L1 (Barley et al, 2009). The role of astroglia in pathogenesis of PD remains to be fully characterized. Astrocytes express monoamine oxidase-B associated with catabolism of catecholamines and dopamine (Ekblom et al, 1993). Increased astrocytic expression of MAO-B in inducible transgenic mouse triggered Parkinsonian symptoms (Siddiqui et al, 2011)
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