BDNF-TrkB signaling in striatopallidal neurons controls inhibition of locomotor behaviour

The physiology of brain-derived neurotrophic factor signaling in enkephalinergic striatopallidal neurons is poorly understood. Changes in cortical Bdnf expression levels, and/or impairment in brain-derived neurotrophic factor anterograde transport induced by mutant huntingtin (mHdh) are believed to cause striatopallidal neuron vulnerability in early-stage Huntington’s disease. Although several studies have confirmed a link between altered cortical brain-derived neurotrophic factor signaling and striatal vulnerability, it is not known whether the effects are mediated via the brain-derived neurotrophic factor receptor TrkB, and whether they are direct or indirect. Using a novel genetic mouse model, here, we show that selective removal of brain-derived neurotrophic factor–TrkB signaling from enkephalinergic striatal targets unexpectedly leads to spontaneous and drug-induced hyperlocomotion. This is associated with dopamine D2 receptor-dependent increased striatal protein kinase C and MAP kinase activation, resulting in altered intrinsic activation of striatal enkephalinergic neurons. Therefore, brain-derived neurotrophic factor/TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior by modulating neuronal activity in response to excitatory input through the protein kinase C/MAP kinase pathway

Acute strength exercise and the involvement of small or large muscle mass on plasma brain‐derived neurotrophic factor levels

OBJECTIVE: Blood neurotrophins, such as the brain-derived neurotrophic factor, are considered to be of great importance in mediating the benefits of physical exercise. In this study, the effect of acute strength exercise and the involvement of small versus large muscle mass on the levels of plasma brain-derived neurotrophic factor were evaluated in healthy individuals. METHODS: The concentric strengths of knee (large) and elbow (small) flexor and extensor muscles were measured on two separate days. Venous blood samples were obtained from 16 healthy subjects before and after exercise. RESULTS: The levels of brain-derived neurotrophic factor in the plasma did not significantly increase after both arm and leg exercise. There was no significant difference in the plasma levels of the brain-derived neurotrophic factor in the arms and legs. CONCLUSION: The present results demonstrate that acute strength exercise does not induce significant alterations in the levels of brain-derived neurotrophic factor plasma concentrations in healthy individuals. Considering that its levels may be affected by various factors, such as exercise, these findings suggest that the type of exercise program may be a decisive factor in altering peripheral brain-derived neurotrophic factor

A single brain-derived neurotrophic factor infusion into the dorsomedial prefrontal cortex attenuates cocaine self-administration-induced phosphorylation of synapsin in the nucleus accumbens during early withdrawal

BACKGROUND: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine-induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. METHODS: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. RESULTS: Two hours after cocaine self-administration, p-synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. CONCLUSIONS: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration–induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal

Effects of Aerobic and Resistance Exercise on Brain-Derived Neurotrophic Factor and Cognitive Benefits in Alzheimer’s Disease

Cognitive function below age-matched controls is the hallmark of Alzheimer’s disease. Brain-Derived Neurotrophic Factor is a biochemical molecule that mediates neuronal survival, but its expression is reduced in Alzheimer’s disease, causing neurodegeneration. Exercise has been shown to increase Brain-Derived Neurotrophic Factor, which mediates improvements in cognition in Alzheimer’s patients and slows cognitive decline. Evidence is presented to show that aerobic exercise is well known to increase serum Brain-Derived Neurotrophic Factor, while resistance training studies have not yet shown a conclusive effect. Increased Brain-Derived Neurotrophic Factor from aerobic exercise has been shown to mediate improvements in hippocampal volume and executive function. No clinical guidelines have been developed for exercise to improve cognition in Alzheimer’s patients, so clinicians are encouraged to follow the Canadian Physical Activity guidelines and include both aerobic and resistance training in exercise programs to achieve maximum cognitive benefits. Exercise prescription is especially important for those at high risk of developing Alzheimer’s disease, as they will greatly benefit from the protective effects of Brain-Derived Neurotrophic Factor before converting and exercise adherence is increased in Alzheimer’s patients if they have found exercise they enjoy

Brain-derived neurotrophic factor in megakaryocytes

The biosynthesis of endogenous BDNF has thus far been examined in neurons where it is expressed at very low levels, in an activity-dependent fashion. In humans, BDNF has long been known to accumulate in circulating platelets, at levels far higher than in the brain. During the process of blood coagulation, BDNF is released from platelets which has led to its extensive use as a readily accessible biomarker, under the assumption that serum levels may somehow reflect brain levels. To identify the cellular origin of BDNF in platelets, we established primary cultures of megakaryocytes, the progenitors of platelets, and found that human and rat megakaryocytes express the BDNF gene. Surprisingly, the pattern of mRNA transcripts is similar to neurons. In the presence of thapsigargin and of external calcium, the levels of the mRNA species leading to efficient BDNF translation rapidly increase. Under these conditions, pro-BDNF, the obligatory precursor of biologically active BDNF, becomes readily detectable. Megakaryocytes store BDNF in α-granules, with more than 80% of them also containing platelet factor 4. By contrast, BDNF is undetectable in mouse megakaryocytes, in line with the absence of BDNF in mouse serum. These findings suggest that alterations of BDNF levels in human serum as reported in studies dealing with depression or physical exercise may primarily reflect changes occurring in megakaryocytes and platelets, including the ability of the latter to retain and release BDNF

Brain-derived neurotrophic factor in asthmatic children

Background: Brain-derived neurotrophic factor (BDNF) regulates the cross-talk between the immune and nervous systems which may play an important role in asthma pathophysiology. Objective: This study was aimed to investigate the relation between BDNF and asthma exacerbation and severity, and to study its possible correlation to eosinophilic counts in blood and sputum. Methods: Twenty-seven asthmatic children were studied during both exacerbation and remission. According to acute exacerbation severity as assessed clinically and by peak expiratory flow rate (PEFR), they were equally subdivided into 3 groups (mild, moderate and severe). Serum and sputum BDNF levels as well as blood and sputum eosinophilic counts were estimated in all patients in comparison to 30 healthy children with no personal or family history of atopy. Results: BDNF levels (in serum and sputum) and eosinophilic counts (in blood and sputum) were significantly elevated in asthmatic patients, whether studied as one group or subgrouped into mild, moderate and severe as compared to controls. Patients with mild, moderate and severe acute asthma exacerbation had significantly higher values of BDNF (in serum and sputum) and eosinophilic count (in blood and sputum) than the corresponding values measured during remission. The latter values were still higher than those of the control group. BDNF in serum and sputum indirectly correlated with asthma severity as evidenced by their negative correlation with PEFR. However, sputum BDNF correlated better with the severity of asthma exacerbation as evidenced directly by its significant increase with clinical severity. Both serum and sputum BDNF levels revealed significant positive correlations with eosinophilic count in blood and sputum among all studied groups. Conclusion: BDNF probably plays a role in the evolution of asthma exacerbation and it reflects the degree of asthma severity during exacerbation. It might also represent an objective indicator of remission and treatment efficacy. Studies with specific BDNF receptor antagonists or synthesis inhibitors are required as BDNF may prove to be a reasonable target for a new therapy in future.Keywords: BDNF, neurotrophins, bronchial asthma, asthma severity, neurogenic inflammationEgypt J Pediatr Allergy Immunol 2003; 1(2): 102-

Brain-derived neurotrophic factor: a new adipokine

Since leptin discovery in 1994, an extensive body of work has been demonstrating that adipose tissue (mainly its white phenotype) expresses not only metabolic, but also endocrine and paracrine phenotypes, particularly in adipobiology of disease. This new biology is achieved predominantly through secretion of adipokines, which include more than hundred highly active signaling proteins. However, studies on adipobiology of neurotrophins have recently emerged, nerve growth factor being one example of adipose-derived neurotrophins. Here we present data showing that brain-derived neurotrophic factor is also expressed in both white and brown adipose tissue.Biomedical Reviews 2007; 18: 85-88

Brain-derived neurotrophic factor released from blood platelets prevents dendritic atrophy of lesioned adult central nervous system neurons

In humans and other primates, blood platelets contain high concentrations of brain-derived neurotrophic factor due to the expression of the BDNF gene in megakaryocytes. By contrast, mice, typically used to investigate the impact of CNS lesions, have no demonstrable levels of brain-derived neurotrophic factor in platelets, and their megakaryocytes do not transcribe significant levels of the Bdnf gene. Here, we explore potential contributions of platelet brain-derived neurotrophic factor with two well-established CNS lesion models, using ‘humanized’ mice engineered to express the Bdnf gene under the control of a megakaryocyte-specific promoter. Retinal explants prepared from mice containing brain-derived neurotrophic factor in platelets were labelled using DiOlistics and the dendritic integrity of retinal ganglion cells assessed after 3 days by Sholl analysis. The results were compared with retinas of wild-type animals and with wild-type explants supplemented with saturating concentrations of brain-derived neurotrophic factor or the tropomyosin kinase B antibody agonist, ZEB85. An optic nerve crush was also performed, and the dendrites of retinal ganglion cells similarly assessed 7-day post-injury, comparing the results of mice containing brain-derived neurotrophic factor in platelets with wild-type animals. In mice engineered to contain brain-derived neurotrophic factor in platelets, the mean serum brain-derived neurotrophic factor levels were 25.74 ± 11.36 ng/mL for homozygous and 17.02 ± 6.44 ng/mL for heterozygous mice, close to those determined in primates. Retinal explants from these animals showed robust preservation of dendrite complexity, similar to that seen with wild-type explants incubated with medium supplemented with brain-derived neurotrophic factor or the tropomyosin receptor kinase B antibody agonist, ZEB85. The Sholl areas under curve were 1811 ± 258, 1776 ± 435 and 1763 ± 256 versus 1406 ± 315 in the wild-type control group (P ≤ 0.001). Retinal ganglion cell survival based on cell counts was similar in all four groups, showing ∼15% loss. A robust neuroprotective effect was also observed following optic nerve crush when assessing the dendrites of the retinal ganglion cells in the transgenic mouse, with Sholl area under the curve significantly higher compared to wild-type (2667 ± 690 and 1921 ± 392, P = 0.026), with no significant difference in the contralateral eye controls. Repeat experiments found no difference in cell survival, with both showing ∼50% loss. These results indicate that platelet brain-derived neurotrophic factor has a strong neuroprotective effect on the dendrite complexity of retinal ganglion cells in both an ex vivo and in vivo model, suggesting that platelet brain-derived neurotrophic factor is likely to be a significant neuroprotective factor in primates

Expression and Function of Neurotrophins and Their Receptors in Cultured Human Keratinocytes

Whereas nerve growth factor has been extensively studied in human keratinocytes, little is known on the role of other members of the neurotrophin family. We investigated the expression and function of neurotrophins and neurotrophin receptors in cultured human keratinocytes. We demonstrated by reverse transcription–polymerase chain reaction that keratinocytes synthesize neurotrophin-3, brain-derived neurotrophic factor, and neurotrophin-4/5. These cells also express tyrosinase kinase A and C, the nerve growth factor and neuro-trophin-3 high-affinity receptors, respectively. On the other hand, only the truncated extracellular isoform of tyrosinase kinase B, the high-affinity brain-derived neurotrophic factor and neurotrophin-4/5 receptor, is detected in keratinocytes. Moreover, neurotrophin-3, brain-derived neurotrophic factor, and neurotrophin-4/5 proteins are secreted by human keratinocytes at low levels. Keratinocyte stem cells synthesize the highest amounts of nerve growth factor, while they secrete higher levels of nerve growth factor as compared with transit amplifying cells. Neurotrophin-3 stimulates keratinocyte proliferation, where brain-derived neurotrophic factor or neurotrophin-4/5 does not exert any effect on keratinocyte proliferation. Addition of neurotrophin-3 slightly upregulates the secretion of nerve growth factor, whereas nerve growth factor strongly augments neurotrophin-3 release. Ultraviolet B irradiation downregulates nerve growth factor, whereas it augments neurotrophin-3 and neurotrophin-4/5 protein levels. Ultraviolet A irradiation increases the level of neurotrophin-3, whereas it does not exert any effect on the other neurotrophins. Finally, neurotrophins other than nerve growth factor fail to protect human keratinocytes from ultraviolet B-induced apoptosis. This work delineates a functional neurotrophin network, which may contribute to epidermal homeostasis