Enhanced Brain-derived Neurotrophic Factor Expression Research Articles

HuD Promotes BDNF Expression in Brain Neurons via Selective Stabilization of the BDNF Long 3′UTR mRNA

Complex regulation of brain-derived neurotrophic factor (BDNF) governs its intricate functions in brain development and neuronal plasticity. Besides tight transcriptional control from multiple distinct promoters, alternative 3′end processing of the BDNF transcripts generates either a long or a short 3′untranslated region (3′UTR). Previous reports indicate that distinct RNA sequence in the BDNF 3′UTRs differentially regulates BDNF production in the brain to accommodate neuronal activity changes, conceivably through differential interactions with undefined trans-acting factors that regulate stability and translation of these BDNF mRNA isoforms. In this study, we report that the neuronal RNA-binding protein (RBP) HuD interacts with a highly conserved AU-rich element (ARE) specifically located in the BDNF long 3′UTR. Such interaction is necessary and sufficient for selective stabilization of mRNAs that contain the BDNF long 3′UTR in vitro and in vivo. Moreover, in a HuD transgenic mouse model, the BDNF long 3′UTR mRNA is increased in the hippocampal dentate granule cells (DGCs), leading to elevated expression of BDNF protein that is transported and stored in the mossy fiber (MF) terminals. Our results identify HuD as the first trans-acting factor that enhances BDNF expression specifically through the long 3′UTR and a novel mechanism that regulates BDNF protein production in selected neuronal populations by HuD abundance.

Yueju Pill Rapidly Induces Antidepressant-Like Effects and Acutely Enhances BDNF Expression in Mouse Brain

The traditional antidepressants have a major disadvantage in delayed onset of efficacy, and the emerging fast-acting antidepressant ketamine has adverse behavioral and neurotoxic effects. Yueju pill, an herb medicine formulated eight hundred years ago by Doctor Zhu Danxi, has been popularly prescribed in China for alleviation of depression-like symptoms. Although several clinical outcome studies reported the relative short onset of antidepressant effects of Yueju, this has not been scientifically investigated. We, therefore, examined the rapid antidepressant effect of Yueju in mice and tested the underlying molecular mechanisms. We found that acute administration of ethanol extract of Yueju rapidly attenuated depressive-like symptoms in learned helpless paradigm, and the antidepressant-like effects were sustained for at least 24 hours in tail suspension test in ICR mice. Additionally, Yueju, like ketamine, rapidly increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, whereas the BDNF mRNA expression remained unaltered. Yueju rapidly reduced the phosphorylation of eukaryotic elongation factor 2 (eEF2), leading to desuppression of BDNF synthesis. Unlike ketamine, both the BDNF expression and eEF2 phosphorylation were revered at 24 hours after Yueju administration. This study is the first to demonstrate the rapid antidepressant effects of an herb medicine, offering an opportunity to improve therapy of depression.

A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex

The dopamine D5 receptor (D5R) exhibits a wide distribution in prefrontal cortex (PFC) but its role in this region has not yet been elucidated. In the present study, we identified a novel physiological function for the D(5)R as a regulator of brain-derived neurotrophic factor (BDNF) and Akt signalling in PFC. Specifically, acute activation of the D(5)R by the dopamine agonist SKF 83959 enhanced BDNF expression and signalling through its receptor, tropomyosin receptor kinase B (TrkB), in rats and in mice gene-deleted for the D1 receptor but not the D(5)R. These changes were concomitant with increased expression of GAD67, a protein whose down-regulation has been implicated in the aetiology of schizophrenia. Furthermore, D(5)R activation increased phosphorylation of Akt at the Ser(473) site, consequently decreasing the activity of its substrate GSK-3β. These findings could have wide-reaching implications given evidence showing activation of these pathways in PFC has therapeutic effects in neuropsychiatric disorders such as drug addiction, schizophrenia and depression.

Physical exercise ameliorates memory impairment in rat pups with maternal lipopolysaccharide-induced cerebral palsy

Maternal lipopolysaccharide (LPS) exposure increases the incidence of cerebral palsy (CP). In the present study, we investigated the effects of treadmill exercise on memory in relation to the expression of brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) in the brain using rat pups of a maternal LPS-induced cerebral palsy model. There were two groups of pregnant rats, an LPS-injection group and a control group. During pregnancy, the rats in the LPS-injection group received a 1 mL intracervical injection of 0.15 mg/kg LPS. After birth, the neonatal rats were divided into three groups: a control group, an LPS-injection group, and a LPS-injection and exercise group. Five weeks after birth, the rat pups in the LPS-injection and exercise group were forced to run on a motorized treadmill for 30 min per day, five times per week for 4 weeks. Rat pups in the maternal LPS injection group showed decreased memory with suppressed BDNF expression, its receptor tyrosine kinase B (TrkB), 5-HT, and its synthesis enzyme tryptophan hydroxylase (TPH). Rat pups in the maternal LPS injection group that exercised showed alleviated memory impairment with enhanced expression of BDNF, TrkB, 5-HT, and TPH. We suggest that treadmill exercise increases 5-HT synthesis in the dorsal raphe, which, in turn, enhances BDNF expression in the hippocampus, resulting in the restoration of memory function. Treadmill exercise may be a useful strategy to mitigate neurodegenerative disorders in offspring that have been induced with an LPS injection during pregnancy.

Exercise can rescue recognition memory impairment in a model with reduced adult hippocampal neurogenesis

Running is a potent stimulator of cell proliferation in the adult dentate gyrus and these newly generated hippocampal neurons seem to be implicated in memory functions. Here we have used a mouse model expressing activated Ras under the direction of the neuronal Synapsin I promoter (named synRas mice). These mice develop down-regulated proliferation of adult hippocampal precursor cells and show decreased short-term recognition memory performances. Voluntary physical activity reversed the genetically blocked generation of hippocampal proliferating cells and enhanced the dendritic arborisation of the resulting doublecortin newly generated neurons. Moreover, running improved novelty recognition in both wild type and synRas littermates, compensating their memory deficits. Brain-derived neurotrophic factor (BDNF) has been proposed to be a potential mediator of physical exercise acting in the hippocampus on dentate neurons and their precursors. This was confirmed here by the identification of doublecortin-immunoreactive cells expressing tyrosine receptor kinase B BDNF receptor. While no difference in BDNF levels were detected in basal conditions between the synRas mice and their wild type littermates, running was associated with enhanced BDNF expression levels. Thus increased BDNF signalling is a candidate mechanism to explain the observed effects of running. Our studies demonstrate that voluntary physical activity has a robust beneficial effect even in mice with genetically restricted neurogenesis and cognition.

Loss of Huntingtin Function Complemented by Small Molecules Acting as Repressor Element 1/Neuron Restrictive Silencer Element Silencer Modulators

Increased levels of the repressor element 1/neuron restrictive silencer element (RE1/NRSE) silencing activity promoter, and a consequent reduction in the transcription of many RE1/NRSE-bearing neuronal genes, including brain-derived neurotrophic factor (BDNF), have been demonstrated in Huntington disease (HD) and represent one possible effector of its selective neuronal vulnerability. Restoring the expression levels of neuronal genes in diseased neurons therefore seems to be an attractive therapeutic approach. To this end, we have developed a cell-based reporter assay for monitoring RE1/NRSE silencing activity and validated it by genetically inactivating the RE1/NRSE or pharmacologically stimulating global transcription. In a pilot compound screen, we identified three closely related structural analogues that up-regulate reporter expression at low nanomolar concentrations, and follow-up studies have shown that they efficaciously increase endogenous BDNF levels in HD cells. Moreover, one of the compounds increases the viability of HD cells. Our findings suggest a new avenue for the development of drugs for HD and other neurodegenerative disorders based on the pharmacological up-regulation of the production of the neuronal survival factor BDNF and of other RE1/NRSE-regulated neuronal genes.

Enhancement of Antidepressant-Like Effects but Not Brain-Derived Neurotrophic Factor mRNA Expression by the Novel N-Methyl-d-aspartate Receptor Antagonist Neramexane in Mice

Improved efficacy in the treatment of depression may be achieved by the combined use of several antidepressants. In the present study, acute administration of the novel N-methyl-D-aspartate (NMDA) receptor antagonist neramexane, as well as the representative antidepressants imipramine, fluoxetine, and venlafaxine, shortened the duration of immobility in the mouse tail suspension test with a minimal effective dose of 5 mg/kg. When tested in combination, the antidepressant-like effects of 5 mg/kg imipramine, 20 mg/kg fluoxetine, and 5 mg/kg venlafaxine were potentiated by neramexane (2.5 mg/kg), a dose that alone did not produce a significant effect on the duration of immobility. These effects seemed to be specific, because they were not accompanied by significant effects on locomotor activity. The enhanced antidepressant-like activity produced with the different combinations was not synergistic as determined by comparing the theoretical and observed ED(50) values for each combination. In separate experiments, Northern blot analysis showed that a 14-day treatment with imipramine (10 mg/kg b.i.d.) increased brain-derived neurotrophic factor (BDNF) mRNA expression in the cortex, whereas neramexane (5 mg/kg b.i.d.) decreased it. Combined treatment produced no effect on BDNF mRNA expression. Mice treated with imipramine or neramexane for 14 days and tested shortly after the last dose demonstrated significant shortening of immobility, and the combined treatment produced an even greater antidepressant-like effect. Together, these data support the view that NMDA receptor antagonists enhance the potency of antidepressants, but they leave open the question as to whether enhanced BDNF expression is a necessary feature of the antidepressant-like effect.