Glucocorticoid receptor represses brain-derived neurotrophic factor expression in neuron-like cells

Abstract

Brain-derived neurotrophic factor (BDNF) is involved in many functions such as neuronal growth, survival, synaptic plasticity and memorization. Altered expression levels are associated with many pathological situations such as depression, epilepsy, Alzheimer’s, Huntington’s and Parkinson’s diseases. Glucocorticoid receptor (GR) is also crucial for neuron functions, via binding of glucocorticoid hormones (GCs). GR actions largely overlap those of BDNF. It has been proposed that GR could be a regulator of BDNF expression, however the molecular mechanisms involved have not been clearly defined yet. Herein, we analyzed the effect of a GC agonist dexamethasone (DEX) on BDNF expression in mouse neuronal primary cultures and in the newly characterized, mouse hippocampal BZ cell line established by targeted oncogenesis. Mouse Bdnf gene exhibits a complex genomic structure with 8 untranslated exons (I to VIII) splicing onto one common and unique coding exon IX. We found that DEX significantly downregulated total BDNF mRNA expression by around 30%. Expression of the highly expressed exon IV and VI containing transcripts was also reduced by DEX. The GR antagonist RU486 abolished this effect, which is consistent with specific GR-mediated action. Transient transfection assays allowed us to define a short 275 bp region within exon IV promoter responsible for GR-mediated Bdnf repression. Chromatin immunoprecipitation experiments demonstrated GR recruitment onto this fragment, through unidentified transcription factor tethering. Altogether, GR downregulates Bdnf expression through direct binding to Bdnf regulatory sequences. These findings bring new insights into the crosstalk between GR and BDNF signaling pathways both playing a major role in physiology and pathology of the central nervous system.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-017-0295-x) contains supplementary material, which is available to authorized users.

Proteomic profiling of the neurons in mice with depressive-like behavior induced by corticosterone and the regulation of berberine: pivotal sites of oxidative phosphorylation

“…Stresslike forced swimming can induce the down-regulation of GR expression in the hippocampus of mice [62], showing the relationship among stress, GC and GR expression. Our results showed CORT can cause the negative feedback inhibition of GR in nerve cells, which in turn influences neural function because GR is mainly related to cell growth, cell survival, and BDNF expression in hippocampal neurons [63]. According to data analysis, the GR gene Nr3c1 can act on the BDNF1 transcriptional promoter region to promote the expression of BDNF1 (https://epd.epfl.ch/cgi-bin/get_doc?db=mmEpd-New&format=genome&entry=Bdnf_1).…”

Evaluation of BDNF levels in patients hospitalized for physical trauma at an emergency hospital in Porto Alegre, southern Brazil

“…18 A recent study has revealed that glucocorticoid receptors downregulate the expression of BDNF. 19 In that study, the authors demonstrated that exposure to dexamethasone suppressed the expression of the transcription of BDNF in neuronal cells mediated by glucocorticoid receptors.…”

Mental Ill-Health and Heart Failure Comorbidity

“…BDNF is present throughout the brain with higher concentrations found in the hippocampus. This area is responsible for cognitive functions, such as learning, behaviour, memorisation, stress, emotions, and mood [21]. It is directly involved in neuroplasticity through regulation of cellular processes; growth, maintenance and survival of the neuronal circuits involved in cognitive and emotional functions, as well as indirectly through its regulation of other processes that can influence neuroplasticity such as depression [22].…”