Brain‐derived neurotrophic factor interacts with astrocytes and neurons to control respiration

Respiratory rhythm is generated and modulated in the brainstem. Neuronal involvement in respiratory control and rhythmogenesis is now clearly established. However, glial cells have also been shown to modulate the activity of brainstem respiratory groups. Although the potential involvement of other glial cell type(s) cannot be excluded, astrocytes are clearly involved in this modulation. In parallel, brain‐derived neurotrophic factor (BDNF) also modulates respiratory rhythm. The currently available data on the respective roles of astrocytes and BDNF in respiratory control and rhythmogenesis lead us to hypothesize that there is BDNF‐mediated control of the communication between neurons and astrocytes in the maintenance of a proper neuronal network capable of generating a stable respiratory rhythm. According to this hypothesis, progression of Rett syndrome, an autism spectrum disease with disordered breathing, can be stabilized in mouse models by re‐expressing the normal gene pattern in astrocytes or microglia, as well as by stimulating the BDNF signaling pathway. These results illustrate how the signaling mechanisms by which glia exerts its effects in brainstem respiratory groups is of great interest for pathologies associated with neurological respiratory disorders.     

The influence of aging on the methylation status of brain‐derived neurotrophic factor gene in blood

Objective

Brain‐derived neurotrophic factor (BDNF) is involved in the pathophysiology of psychiatric disorders in adults and elderly individuals, and as a result, the DNA methylation (DNAm) of the BDNF gene in peripheral tissues including blood has been extensively examined to develop a useful biomarker for psychiatric disorders. However, studies to date have not previously investigated the effect of age on DNAm of the BDNF gene in blood. In this context, we measured DNAm of 39 CpG units in the CpG island at the promoter of exon I of the BDNF gene.

Methods

We analyzed genomic DNA from peripheral blood of 105 health Japanese women 20 to 80 years of age to identify aging‐associated change in DNAm of the BDNF gene. In addition, we examined the relationship between total MMSE scores, numbers of stressful life events, and serum BDNF levels on DNAm of the BDNF gene. The DNAm rate at each CpG unit was measured using a MassArray^® system (Agena Bioscience), and serum BDNF levels were measured by ELISA.

Results

There was a significant correlation between DNAm and age in 13 CpGs. However, there was no significant correlation between DNAm and total MMSE scores, numbers of life events, or serum BDNF levels.

Conclusion

Despite the small number of subjects and the inclusion of only female subjects, our results suggest that DNAm of 13 CpGs of the BDNF gene may be an appropriate biomarker for aging and useful for predicting increased susceptibility to age‐related psychiatric disorders.     

Electrically induced brain‐derived neurotrophic factor release from schwann cells

Regulating the production of brain‐derived neurotrophic factor (BDNF) in Schwann cells (SCs) is critical for their application in traumatic nerve injury, neurodegenerative disorders, and demyelination disease in both central and peripheral nervous systems. The present study investigated the possibility of using electrical stimulation (ES) to activate SCs to release BDNF. We found that short‐term ES was capable of promoting BDNF production from SCs, and the maximal BDNF release was achieved by ES at 6 V (3 Hz, 30 min). We further examined the involvement of intracellular calcium ions ([Ca₂₊]_i) in the ES‐induced BDNF production in SCs by pharmacological studies. We found that the ES‐induced BDNF release required calcium influx through T‐type voltage‐gated calcium channel (VGCC) and calcium mobilization from internal calcium stores, including inositol triphosphate‐sensitive stores and caffeine/ryanodine‐sensitive stores. In addition, calcium‐calmodulin dependent protein kinase IV (CaMK IV), mitogen‐activated protein kinase (MAPK), and cAMP response element‐binding protein (CREB) were found to play important roles in the ES‐induced BDNF release from SCs. In conclusion, ES is capable of activating SCs to secrete BDNF, which requires the involvement of calcium influx through T‐type VGCC and calcium mobilization from internal calcium stores. In addition, activation of CaMK IV, MAPK, and CREB were also involved in the ES‐induced BDNF release. The findings indicate that ES can improve the neurotrophic ability in SCs and raise the possibility of developing electrically stimulated SCs as a source of cell therapy for nerve injury in both peripheral and central nervous systems. © 2014 Wiley Periodicals, Inc.     

Blocking brain‐derived neurotrophic factor inhibits injury‐induced hyperexcitability of hippocampal CA3 neurons

Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin‐related kinase B (TrkB), a receptor for brain‐derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF‐mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury‐induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB‐Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB‐Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two‐fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB‐Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB‐Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury‐induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post‐traumatic epilepsy. Therefore, our data suggest that blocking the BDNF–TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post‐traumatic epilepsy.     

The effect of acute exercise on blood concentrations of brain‐derived neurotrophic factor in healthy adults: a meta‐analysis

It has been hypothesized that one mechanism through which physical activity provides benefits to cognition and mood is via increasing brain‐derived neurotrophic factor (BDNF) concentrations. Some studies have reported immediate benefits to mood and various cognitive domains after a single session of exercise. This meta‐analysis sought to determine the effect of a single exercise session on concentrations of BDNF in peripheral blood, in order to evaluate the potential role of BDNF in mediating the beneficial effects of exercise on brain health. MEDLINE, Embase, PsycINFO, SPORTDiscus, Rehabilitation & Sports Medicine Source, and CINAHL databases were searched for original, peer‐reviewed reports of peripheral blood BDNF concentrations before and after acute exercise interventions. Risk of bias within studies was assessed using standardized criteria. Standardized mean differences (SMDs) were generated from random effects models. Risk of publication bias was assessed using a funnel plot and Egger's test. Potential sources of heterogeneity were explored in subgroup analyses. In 55 studies that met inclusion criteria, concentrations of peripheral blood BDNF were higher after exercise (SMD = 0.59, 95% CI: 0.46–0.72, P < 0.001). In meta‐regression analysis, greater duration of exercise was associated with greater increases in BDNF. Subgroup analyses revealed an effect in males but not in females, and a greater BDNF increase in plasma than serum. Acute exercise increased BDNF concentrations in the peripheral blood of healthy adults. This effect was influenced by exercise duration and may be different across genders.     

Effects of antidepressant treatment on mice lacking brain‐derived neurotrophic factor expression through promoter IV

Brain‐derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depression; mice lacking BDNF expression through promoter IV (BDNF‐KIV) exhibit a depression‐like phenotype. We tested our hypothesis that deficits caused by promoter IV deficiency (depression‐like behavior, decreased levels of BDNF, and neurogenesis in the hippocampus) could be rescued by a 3‐week treatment with different types of antidepressants: fluoxetine, phenelzine, duloxetine, or imipramine. Each antidepressant reduced immobility time in the tail suspension test without affecting locomotor activity in the open field test in both BDNF‐KIV and control wild type mice, except that phenelzine increased locomotor activity in wild type mice and anxiety‐like behavior in BDNF‐KIV mice. The antidepressant treatments were insufficient to reverse decreased BDNF levels caused by promoter IV deficiency. No antidepressant treatment increased the hippocampal progenitors of either genotype, whereas phenelzine decreased the surviving progenitors in both genotypes. The antidepressant treatments differently affected the dendritic extension of hippocampal immature neurons: fluoxetine and imipramine increased extension in both genotypes, duloxetine increased it only in BDNF‐KIV mice, and phenelzine decreased it only in wild type mice. Interestingly, a saline‐only injection increased neurogenesis and dendrite extensions in both genotypes. Our results indicate that the behavioral effects in the tail suspension test by antidepressants do not require promoter IV‐driven BDNF expression and occur without a detectable increase in hippocampal BDNF levels and neurogenesis but may involve increased dendritic reorganisation of immature neurons. In conclusion, the antidepressant treatment demonstrated limited efficacy; it partially reversed the defective phenotypes caused by promoter IV deficiency but not hippocampal BDNF levels.     

Effects of moderate‐ and high‐intensity chronic exercise on brain‐derived neurotrophic factor expression in fast and slow muscles

Introduction: Brain‐derived neurotrophic factor (BDNF) protein expression is sensitive to cellular activity. In the sedentary state, BDNF expression is affected by the muscle phenotype. Methods: Eighteen Wistar rats were divided into the following 3 groups: sedentary (S); moderate‐intensity training (MIT); and high‐intensity training (HIT). The training protocol lasted 8 weeks. Forty‐eight hours after training, total RNA and protein levels in the soleus and plantaris muscles were obtained. Results: In the plantaris, the BDNF protein level was lower in the HIT than in the S group (P < 0.05). A similar effect was found in the soleus (without significant difference). In the soleus, higher Bdnf mRNA levels were found in the HIT group (P < 0.001 vs. S and MIT groups). In the plantaris muscle, similar Bdnf mRNA levels were found in all groups. Conclusions: These results indicate that high‐intensity chronic exercise reduces BDNF protein level in fast muscles and increases Bdnf mRNA levels in slow muscles. Muscle Nerve 53: 446–451, 2016     

The val66met polymorphism of brain‐derived neurotrophic factor is associated with human esophageal hypersensitivity

Background Recent evidence implicates brain‐derived neurotrophic factor (BDNF) in visceral hypersensitivity and pain in functional gastrointestinal disorders. We hypothesized that presence of the val66met polymorphism in the BDNF gene would be linked to increased esophageal sensitivity to electrical stimulation. Methods A total of 39 healthy volunteers (20 males, mean age 30) compliant with inclusion criteria after screening procedures were genotyped for BDNF polymorphisms and completed an Hospital Anxiety and Depression Scale (HADS) questionnaire. Sensory (ST) and pain (PT) thresholds in the proximal (PE) and distal (DE) esophagus were determined using electrical stimuli to a swallowed intraluminal catheter with bipolar electrodes by an investigator blinded to the subjects’ genotype. For comparison, somatic ST and PT (hand and foot) were also tested. HADS scores together with esophageal and somatic thresholds were then correlated with BDNF polymorphism status. Key Results Eleven of 39 (28%) volunteers had at least one Met allele (Met carriers). When compared with Val/Val, Met carriers had lower esophageal PT (Median PT [mA]: Val/Val vs Met carriers, PE; 49.4 vs 44.3, P = 0.033, DE: 63.8 vs 55.4, P = 0.045) with higher proportion of Val/Val subjects in the upper quartile for PT in both PE (P = 0.021) and DE (P = 0.033), yet similar somatic PT (Median PT [mA] Hand; 33.6 vs 38.0, P = 0.22, Foot; 44.7 vs 44.0, P = 0.48). Sensitivity results were independent of anxiety (P = 0.66) and depression (P = 0.33) scores. Conclusions & Inferences val66met BDNF polymorphisms are associated with increased esophageal sensitivity to experimental electrical stimulation. Thus, BDNF genotype may be a useful biomarker for electrical sensitivity in the healthy human esophagus.     

Furin mediates brain‐derived neurotrophic factor upregulation in cultured rat astrocytes exposed to oxygen–glucose deprivation

This study investigated the changes in brain‐derived neurotrophic factor (BDNF) expression and the role of furin in BDNF maturation in reactive astrocytes from rats exposed to oxygen–glucose deprivation (OGD). Furin, a proprotein convertase, is upregulated and cleaves certain substrates during hypoxia in cancer cells. In addition, during hypoxia in the central nervous system, astrocytes become reactive and release BDNF to protect neurons. Maturation of BDNF in astrocytes requires furin‐mediated endoproteolytic processing of the precursor protein pro‐BDNF to BDNF. To expand our knowledge about the role of furin in BDNF maturation in astrocytes, these cells were exposed to OGD, and expression of furin and BDNF was detected by Western blot analysis. Changes in BDNF expression were observed when furin activity was inhibited by furin prosegment. We found that protein expression of BDNF and furin was upregulated, and this upregulation correlated with OGD stimulation. Furin inhibition reduced BDNF maturation and secretion. These results indicate that furin mediates the upregulation of BDNF in reactive astrocytes exposed to OGD and that furin may impact the biological effect of reactive astrocytes. © 2014 Wiley Periodicals, Inc.     

Ginsenoside Rg1 reverses stress‐induced depression‐like behaviours and brain‐derived neurotrophic factor expression within the prefrontal cortex

Depression is a major neuropsychiatric disorder that exerts deleterious effects upon public health. However, the neuronal mechanisms of depression remain largely uncharacterized, which has retarded the identification and development of effective therapeutic tools for the treatment of this disorder. The aim of this study was to explore the neuronal mechanisms underlying the protective effects of ginsenoside Rg1, a natural steroidal saponin found in ginseng, against chronic stress‐induced depression.The results showed that chronic administration of ginsenoside Rg1 (40 mg/kg, i.p., 5 weeks) significantly ameliorated depression‐like behaviours in rats as assessed in the sucrose preference and forced swim tests. Furthermore, chronic stress decreased the phosphorylation levels of the extracellular signal‐regulated kinase and cAMP‐response element‐binding protein in the prefrontal cortex as well as producing a reduction of brain‐derived neurotrophic factor expression. Of particular importance, all reductions in these parameters were significantly reversed by pre‐treatment with ginsenoside Rg1. Taken together, the results of the present study suggest that the antidepressant‐like effect of ginsenoside Rg1 might be mediated, at least in part, by activating the cAMP‐response element‐binding protein–brain‐derived neurotrophic factor system within the prefrontal cortex. These findings not only reveal some of the underlying neuronal mechanisms of depression, but also the therapeutic potential of ginsenoside Rg1 as a preventive agent in the treatment of depression.     

P2X4 receptor in the dorsal horn partially contributes to brain‐derived neurotrophic factor oversecretion and toll‐like receptor‐4 receptor activation associated with bone cancer pain

Previous studies have suggested that the microglial P2X7 purinoceptor is involved in the release of tumor necrosis factor‐α (TNFα) following activation of toll‐like receptor‐4 (TLR4), which is associated with nociceptive behavior. In addition, this progress is evoked by the activation of the P2X4 purinoceptor (P2X4R). Although P2X4R is also localized within spinal microglia in the dorsal horn, little is known about its role in cancer‐induced bone pain (CIBP), which is in some ways unique. With the present rat model of CIBP, we demonstrate a critical role of the microglial P2X4R in the enhanced nociceptive transmission, which is associated with TLR4 activation and secretion of brain‐derived neurotrophic factor (BDNF) and TNFα in the dorsal horn. We assessed mechanical threshold and spontaneous pain of CIBP rats. Moreover, P2X4R small interfering RNA (siRNA) was administered intrathecally, and real‐time PCR, Western blots, immunofluorescence histochemistry, and ELISA were used to detect the expression of P2X4R, TLR4, OX‐42, phosphorylated‐p38 MAPK (p‐p38), BDNF, and TNFα. Compared with controls, intrathecal injection of P2X4R siRNA could prevent nociceptive behavior induced by ATP plus lipopolysaccharide and CIBP and reduce the expression of P2X4R, TLR4, p‐p38, BDNF, and TNFα. In addition, the increase of BDNF protein in rat microglial cells depended on P2X4 receptor signaling, which is partially associated with TLR4 activation. The ability of microglial P2X4R to activate TLR4 in spinal cord leading to behavioral hypersensitivity and oversecretion of BDNF could provide an opportunity for the prevention and treatment of CIBP. © 2014 Wiley Periodicals, Inc.