Decrease of gene expression of astrocytic 5-HT2B receptors parallels development of depressive phenotype in a mouse model of Parkinson’s disease

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.

l-Dopa and Fluoxetine Upregulate Astroglial 5-HT2B Receptors and Ameliorate Depression in Parkinson’s Disease Mice

“…Previously, we reported that the decrease of gene expression of astrocytic 5-HT 2B receptor parallels the development of depressive behavior in the MPTP mouse model of PD, while fluoxetine ameliorates both the decrease in 5-HT 2B receptor expression and anhedonia [13]. In this study, we describe similar results obtained in 6-OHDA mouse model of PD.…”

“…After intraperitoneal injection (which we used in a previous study), MPTP spreads throughout the brain. Astrocytes thus may be affected directly by the drug as we have seen in cultured astrocytes [13], irrespective to the deficiency of dopaminergic system. In this study, we used 6-OHDA, a compound that cannot cross the BBB.…”

“…Recently, we also found a decrease in gene expression of astrocytic but not neuronal 5-HT 2B receptor in animals that received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and became anhedonic. Fluoxetine corrected MPTP-induced decrease of 5-HT 2B receptor expression and depressive behavior [13]. These findings indicate that changes in gene expression of 5-HT 2B receptors in astroglia may be associated with pathophysiological evolution of depression in PD.…”

“…We have shown that downregulation of the gene expression of 5-HT 2B receptors occurs specifically in astrocytes in parallel with the development of depressive behavior in both 6-OHDA and MPTP animal models of PD. The relevance of 5-HT 2B receptors to depression is corroborated by (1) the decrease of its gene expression in the nervous tissue of animals developing depressive behavior under the CMS [11,57], in the MPTP PD animal model [13], and in the 6-OHDA PD animal model; (2) the upregulation of 5-HT 2B receptor gene expression by chronic treatment with fluoxetine in astrocytes in cultures and freshly isolated from the in vivo brains [11,57]; and (3) the dependence of antidepressant effect of fluoxetine on 5-HT 2B receptors in vivo [58]. Since both drugs directly decrease expression of 5-HT 2B receptors in cultured astrocytes, there is still a possibility that this phenomenon may only occur in PD animal models.…”

“…All experimental techniques were essentially similar to those employed in our previous studies of astroglial 5-HT 2B receptors [11][12][13]. All experiments were carried out in accordance with the USA National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No.…”