Brain-derived neurotrophic factor: linking fear learning to memory consolidation

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in synaptic plasticity. In this issue of Molecular Pharmacology, Ou and Gean (p. 350) thoroughly describe the molecular cascade by which fear learning leads to an increase in BDNF expression in the lateral amygdala (LA). Calcium influx through N-methyl-D-aspartate receptors and L-type voltage-dependent calcium channels, which occurs in the LA during fear conditioning, activates protein kinase A and Ca2+/calmodulin-dependent protein kinase IV. Each induces phosphorylation of cAMP response element-binding protein, which binds to the BDNF promoter, leading to BDNF expression in the LA, and contributes to fear memory consolidation.     

Tianeptine increases brain-derived neurotrophic factor expression in the rat amygdala

Chronic restraint stress affects hippocampal and amygdalar synaptic plasticity as determined by electrophysiological, morphological and behavioral measures, changes that are inhibited by some but not all antidepressants. The efficacy of some classes of antidepressants is proposed to involve increased phosphorylation of cAMP response element binding protein (CREB), leading to increased expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). Conversely, some studies suggest that acute and chronic stress downregulate BDNF expression and activity. Accordingly, the aim of the current study was to examine total and phosphorylated CREB (pCREB), as well as BDNF mRNA and protein levels in the hippocampus and amygdala of rats subjected to chronic restraint stress in the presence and absence of the antidepressant tianeptine. In the hippocampus, chronic restraint stress increased pCREB levels without affecting BDNF mRNA or protein expression. Tianeptine administration had no effect upon these measures in the hippocampus. In the amygdala, BDNF mRNA expression was not modulated in chronic restraint stress rats given saline in spite of increased pCREB levels. Conversely, BDNF mRNA levels were increased in the amygdala of chronic restraint stress/tianeptine rats in the absence of changes in pCREB levels when compared to non-stressed controls. Amygdalar BDNF protein increased while pCREB levels decreased in tianeptine-treated rats irrespective of stress conditions. Collectively, these results demonstrate that tianeptine concomitantly decreases pCREB while increasing BDNF expression in the rat amygdala, increases in neurotrophic factor expression that may participate in the enhancement of amygdalar synaptic plasticity mediated by tianeptine.     

Exogenous gangliosides increase the release of brain-derived neurotrophic factor

Gangliosides are lipophilic compounds found in cell plasma membranes throughout the brain that play a role in neuronal plasticity and regeneration. Indeed, absence or abnormal accumulation of gangliosides has been shown to lead to neurological disorders. Experimental data have shown that exogenous gangliosides exhibit properties similar to the neurotrophins, a family of neurotrophic factors that are important in the survival and maintenance of neurons and prevention of neurological diseases. Brain-derived neurotrophic factor (BDNF) is the most abundant of the neurotrophins. This work was done to reveal the neurotrophic mechanism of exogenous gangliosides. In particular, we examined whether gangliosides promote the release of BDNF. Rat hippocampal neurons or human neuroblastoma cells were transduced with a recombinant adenovirus expressing BDNF-flag to facilitate detection of BDNF. Release of BDNF was then determined by Western blot analysis and a two-site immunoassay of culture medium. The depolarizing agent KCl was used as a comparison. In hippocampal neurons, both GM1 ganglioside and KCl evoked within minutes the release of mature BDNF. In human cells, GM1 and other gangliosides released both mature BDNF and pro-BDNF. The effect of gangliosides was structure-dependent. In fact, GT1b preferentially released mature BDNF whereas GM1 released both mature and pro-BDNF. Ceramide and sphingosine did not modify the release of BDNF. This work provides additional experimental evidence that exogenous gangliosides can be used to enhance the neurotrophic factor environment and promote neuronal survival in neurological diseases. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

脑源性神经营养因子在炎症性肠病中的作用

脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）是神经营养因子（neurotrophin,NT）家族中的重要成员,在神经元的维持和存活,保持突触完整性和突触可塑性中起重要作用,但其作用不仅限于此。研究发现BDNF在炎症性肠病（inflammatory bowel disease,IBD）中具有维持内脏超敏反应,促进肠道动力,维持肠道屏障,调节情绪障碍及心脏功能的作用,可能在IBD的发生发展中起重要作用。虽然目前大多限于基础研究,但已经取得了一定的成果,可以预见BDNF将有很好的临床应用前景,可能为IBD的临床治疗提供新的治疗思路。对此,本文作一简要综述。     

Recombinant human brain-derived neurotrophic factor (rHuBDNF)

Three disulfide linkages of recombinant human brain-derived neurotrophic factor (BDNF) were determined by peptide sequence analysis and characterized by mass spectrometry. The three disulfide bonds for BDNF expressed in Chinese hamster ovary cells include Cys-13-Cys-80, Cys-58-Cys-109 and Cys-68-Cys-111, and the disulfide structure was homologous to that of nerve growth factor.     

脑源性生长因子参与疼痛-抑郁共病的研究进展

疼痛和抑郁症存在共病联系,两者之间可能存在共同的神经解剖机制及分子机制。近年来研究发现,中枢神经系统中的脑源性生长因子(brain-derived neurotrophic factor,BDNF)在疼痛-抑郁共病过程中发挥重要作用,BDNF也逐渐成为疼痛及抑郁症的研究热点及治疗靶点。该文就BDNF参与疼痛-抑郁共病的机制及外周血BDNF在疼痛、抑郁症的诊治中的意义做论述。     

Repeated electroconvulsive stimuli increase brain-derived neurotrophic factor in ACTH-treated rats

Electroconvulsive therapy is considered to be an effective treatment for severe depression. We have already shown that the antidepressant-like effects of tricyclic antidepressants in the rat forced swim test are blocked by repeated treatment with adrenocorticotropic hormone (ACTH). In the present study, we investigated the effect of repeated electroconvulsive stimuli on the forced swim test and on brain-derived neurotrophic factor (BDNF) protein levels in ACTH-treated rats. Electroconvulsive stimuli (50 mA, 0.2 s) was administered 30 min after ACTH treatment (100 microg/rat, s.c.) once daily for 14 days. In both saline and ACTH-treated rats, repeated electroconvulsive stimuli for 6 or 14 days decreased the immobility time in the forced swim test and increased the BDNF protein levels in the hippocampus. However, repeated imipramine administration (10 mg/kg, i.p. for 14 days) had no effect on the hippocampus BDNF protein levels in ACTH-treated rats. These results suggest that electroconvulsive stimuli has decreasing effects of immobility time in the forced swim test in the tricyclic antidepressant-resistant depressive model of rats induced by repeated ACTH treatment, and that increased BDNF may be involved in this phenomenon.     

Transport of brain-derived neurotrophic factor across the blood–brain barrier

Brain-derived neurotrophic factor (BDNF) is a potential therapeutic agent for degenerative disorders of the central nervous system. In this report, we investigated the ability of BDNF to cross the blood–brain barrier (BBB). BDNF was stable in blood up to 60 min after i.v. injection, with evidence for aggregation, and had an early, rapid influx into brain. By 10 min, most of the BDNF sequestered by the cerebral cortex was associated with the parenchyma rather than with the endothelial cells, demonstrating complete passage across the BBB. A small dose of unlabeled BDNF enhanced the entry of ¹²⁵I-BDNF from blood to brain after an i.v. bolus injection, whereas larger doses had no effect. In contrast, a large dose of unlabeled BDNF inhibited the influx of ¹²⁵I-BDNF during in situ brain perfusion. After intracerebroventricular injection, the efflux of BDNF from brain to blood occurred at a rate similar to that for reabsorption of cerebrospinal fluid, and no evidence for self-inhibition was found. Therefore, we conclude that intact BDNF in the peripheral circulation crosses the BBB by a high-capacity, saturable transport system.     

Zinc treatment induces cortical brain-derived neurotrophic factor gene expression

Most of antidepressants induce expression of the gene coding for brain-derived neurotrophic factor (BDNF) in the hippocampal/cortical neurons. Recent data indicate antidepressant-like activity of zinc in animal models. We now report that chronic treatment with zinc induced an increase in cortical but not hippocampal BDNF mRNA level (Northern blot). Tranylcypromine, a classic antidepressant, increased BDNF mRNA level in both examined brain regions. This is the first demonstration that zinc increases the BDNF gene expression, which is the effect shared by most of clinically effective antidepressants.     

BDNF在局部脑缺血大鼠的表达

目的 观察大鼠脑缺血后脑源性神营养因子(BDNF)含量的变化.方法 用大鼠大脑中动脉线栓法(MCAO)建立脑缺血模型,免疫组织化学观察BDNF在不同时间点表达变化.结果 与假手术组比较,脑缺血模型组大鼠BDNF在MCAO后缺血6 h表达增强(P＞0.05),48 h达高峰(P＜0.05).结论 脑缺血后神经元内BDNF含量增多,可有利丁受损神经元的修复.     

脑源性神经营养因子与脑卒中后疼痛和抑郁的关系

脑源性神经营养因子（BDNF）是成人脑内含量最丰富的神经营养因子,具有显著的脑损伤修复能力。最近的多项研究表明,BNDF在脑卒中后的多种并发症的发生发展中起到了重要的作用,有希望成为新的卒中治疗方法的晚期靶点,但它的作用机制尚不明确。本文就BDNF的生物学特性、在卒中后并发症的作用机制以及最新的研究进展进行综述,从而为...     

脑源性神经营养因子在抑郁症发生和治疗中的研究进展

目前临床常用的抗抑郁药主要通过增加脑内突触间隙单胺类递质的浓度、增强单胺类神经的功能而起效,但这一机制不能很好地解释抗抑郁药存在的起效时间长等现象.近年提出,抗抑郁药可能还通过增加海马区域脑源性神经营养因子(BDNF)基因表达起效.抗抑郁药能增加受试动物海马区BDNF基因表达,抑郁患者接受抗抑郁药治疗,其血清BDNF水平上升;BDNF基因的单核苷酸多态性也与抑郁症的发生有关;抗抑郁药可能还通过激活丝裂原活化蛋白激酶(MAPK)信号通路,磷酸化cAMP反应序列结合(cREB)蛋白,最终使BDNF基因表达上调.这一机制的提出为抑郁症生物学病因的阐明提供了必要信息,同时也有助于抗抑郁新药的开发,为研制安全、有效的新药提供新的思路.     

Effect of MPEP treatment on brain-derived neurotrophic factor gene expression

Treatment with most antidepressants induces expression of the gene coding for brain-derived neurotrophic factor (BDNF) in the hippocampus (and cerebral cortex). Recent data indicate antidepressant-like activity of group I mGlu receptor (mGluR1 and mGluR5) antagonists in animal tests/models. We now report that chronic treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective mGlu5 receptor antagonist, increased hippocampal but reduced cortical BDNF mRNA level (Northern blot). Desipramine, a classic antidepressant, increased BDNF mRNA level in both examined brain regions. This is the first demonstration that an antagonist of mGlu5 receptors, like a majority of well-established antidepressants, induces hippocampal BDNF gene expression. A significance of MPEP ability to reduce cortical BDNF needs further study. Nevertheless, this observation further indicates a potential antidepressant activity of the group I mGlu receptor antagonists in human depression.     

Chronic ketamine use increases serum levels of brain-derived neurotrophic factor

Rationale  

Ketamine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist which interferes with the action of excitatory amino acids (EAAs) including glutamate and aspartate. The use of ketamine at subanaesthetic doses has increased because of its psychotomimetic properties. However, long-term ketamine abuse may interfere with memory processes and inhibit the induction of long-term potentiation (LTP) in the hippocampus, an effect probably mediated by its NMDA antagonist action. Neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) serve as survival factors for selected populations of central nervous system neurons, including cholinergic and dopaminergic neurons. In addition, neurotrophins, particularly BDNF, may regulate LTP in the hippocampus and influence synaptic plasticity.     

The brain-derived neurotrophic factor gene in suicidal behaviour: a meta-analysis

Suicide is a prominent public health problem. Its aetiology is complex, and the brain-derived neurotrophic factor (BDNF) has been implicated. We performed the first meta-analysis of the functional BDNF marker Val??Met (rs6265, 196G>A) in suicidal behaviour using data from 11 previously published samples plus our present sample (total n=3352 subjects, 1202 with history of suicidal behaviour. The meta-analysis including all 12 studies showed a trend for the Met-carrying genotypes and Met allele conferring risk for suicide (random-effects model p=0.096; ORMet-carrier=1.13, 95% CI 0.98-1.30, and random-effects model p=0.032; ORMet=1.16, 95% CI 1.01-1.32, respectively). Furthermore, we found the Met allele and the Met allele-carrying genotypes to be associated with history of suicide attempt (eight studies; allelic meta-analysis--random-effects model: p=0.013; fixed-effects model: p=0.006; genotypic meta-analysis--random-effects model: p=0.017; fixed-effects model: p=0.008). Taken together, the results from our study suggest that BDNF Val??Met is involved in suicidality. Further studies are required to elucidate its role in suicidal behaviour.     

Long-term potentiation in the amygdala: a cellular mechanism of fear learning and memory

Much of the research on long-term potentiation (LTP) is motivated by the question of whether changes in synaptic strength similar to LTP underlie learning and memory. Here we discuss findings from studies on fear conditioning, a form of associative learning whose neural circuitry is relatively well understood, that may be particularly suited for addressing this question. We first review the evidence suggesting that fear conditioning is mediated by changes in synaptic strength at sensory inputs to the lateral nucleus of the amygdala. We then discuss several outstanding questions that will be important for future research on the role of synaptic plasticity in fear learning. The results gained from these studies may shed light not only on fear conditioning, but may also help unravel more general cellular mechanisms of learning and memory.