Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain-derived neurotrophic factor (BDNF) acutely modulates synaptic transmission to excitatory neurons in hippocampus and neocortex. The question of whether BDNF acts similarly on excitatory synaptic transmission to GABAergic neurons was eluded in previous studies using cortical slices. To address this question, we used transgenic mice in which expression of green fluorescence protein (GFP) is regulated by glutamic acid decarboxylase 67 (GAD67) promoter. In cortical slices prepared from these GAD67-GFP knock-in mice, we could detect GABAergic neurons under a fluorescent microscope. An application of BDNF rapidly depressed excitatory postsynaptic currents (EPSCs) evoked by layer IV stimulation in most GFP-positive neurons in layer II/III of the cortex. This effect was seen at synapses activated during the BDNF application and blocked by anti-TrkB IgG, indicating that the acute inhibitory action of BDNF is activity-dependent and mediated through TrkB. Paired-pulse ratios of the amplitude of EPSCs to paired stimulation at intervals of 10-100 ms were not significantly changed after BDNF application, suggesting that the site of depression may be postsynaptic. Responses to directly applied glutamate were also depressed by BDNF in most of neurons, being consistent with the interpretation of postsynaptic action of BDNF. The depressive action of BDNF was blocked by an intracellular injection of a Ca(2+) chelator, suggesting that a rise in Ca(2+) is involved in the acute depression of EPSCs. This action of BDNF was seen in 67% of parvalbumin (PV)-positive neurons, but in only 19% of PV-negative neurons, indicating that the depressive action is biased to PV-positive GABAergic neurons.
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PMID:Brain-derived neurotrophic factor acutely depresses excitatory synaptic transmission to GABAergic neurons in visual cortical slices. 1525 81

Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain. These two signals co-regulate one another such that 5-HT stimulates the expression of BDNF, and BDNF enhances the growth and survival of 5-HT neurons. Impaired 5-HT and BDNF signaling is central to depression and anxiety disorders, but could also play important roles in the pathogenesis of several age-related disorders, including insulin resistance syndrome, Alzheimer's disease and Huntington's disease. Enhancement of BDNF signaling may be a key mechanism whereby cognitive stimulation, exercise, dietary restriction and antidepressant drugs preserve brain function during aging. Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging.
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PMID:BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. 1537 69

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has antidepressant-like effects in animals. BDNF gene polymorphisms have been associated with bipolar disorder. We tested two genetic polymorphisms of BDNF for their association with childhood-onset mood disorders (COMD) within the context of a case-control design. Two BDNF polymorphisms, a dinucleotide repeat (GT)(n), and a single nucleotide polymorphism (SNP) in the coding region, val66met, were genotyped in 99 adults with a history of COMD and matched psychiatrically healthy controls. A genomic control (GC) method was used to evaluate population substructure. Alleles at (GT)(n) were highly associated with COMD in this sample (chi(2) = 17.8; d.f. = 5; P = 0.0032). The odds of carrying the 168 bp allele were 3.94 times greater for cases than controls (CI = 1.72-9.04). Alleles of val66met were not significantly associated with COMD. GC analysis suggested population substructure was not a confounder of association. Analysis of haplotypes, in which (GT)(n) was treated as a binary variable (long vs. short alleles), provided significant evidence that the haplotype val/short contributes to liability to COMD. The BDNF (GT)(n) marker and the val/short haplotype are associated with COMD in this sample, in accordance with the previously described neurotrophic hypothesis of depression and some previous studies of association for bipolar disorder and neuroticism.
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PMID:Association study of brain-derived neurotrophic factor in adults with a history of childhood onset mood disorder. 1538 83

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of trophic factors. BDNF is widely and abundantly expressed in the CNS and is available to some peripheral nervous system neurons that uptake the neurotrophin produced by peripheral tissues. BDNF promotes survival and differentiation of certain neuronal populations during development. In adulthood, BDNF can modulate neuronal synaptic strength and has been implicated in hippocampal mechanisms of learning and memory and spinal mechanisms for pain. Several CNS disorders are associated with a decrease in trophic support. As BDNF and its high affinity receptor are abundant throughout the whole CNS, and BDNF is a potent neuroprotective agent, this trophic factor is a good candidate for therapeutic treatment of some of CNS disorders. This review aims to correlate the features of some CNS disorders (Parkinson's disease, Alzheimer's disease, depression, epilepsy and chronic pain) to changes in BDNF expression in the brain. The cellular and molecular mechanism by which BDNF might be a therapeutic strategy are critically examined.
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PMID:Brain-derived neurotrophic factor as a drug target for CNS disorders. 1546 90

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family which interacts with high-affinity protein kinase receptors (Trk) and the unselective p75(NGFR) receptor. The BDNF gene has a complex structure with multiple regulatory elements and four promoters that are differentially expressed in central or peripheral tissue. BDNF expression is regulated by neuronal activity or peripheral hormones. Neurotrophins regulate the survival and differentiation of neurons during development but growing evidence indicates that they are also involved in several functions in adulthood, including plasticity processes. BDNF expression in the central nervous system (CNS) is modified by various kinds of brain insult (stress, ischemia, seizure activity, hypoglycemia, etc.) and alterations in its expression may contribute to some pathologies such as depression, epilepsy, Alzheimer's, and Parkinson's disease. Apart from very traumatic situations, the brain functioning is resilient to stress and capable of adaptive plasticity. Neurotrophins might act as plasticity mediators enhancing this trait which seems to be crucial in adaptive processes. In addition to documenting all of the topics mentioned above in the CNS, we review the state of the art concerning neurotrophins and their receptors, including our personal contribution which is essentially focused on the stress response.
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PMID:Physiology of BDNF: focus on hypothalamic function. 1557 56

Understanding the etiology and pathogenesis schizophrenia and depression is a major challenge facing psychiatry. One hypothesis is that these disorders are secondary to a malfunction of neurotrophic factors. Inappropriate neurotrophic support during brain development could lead to structural disorganisation in which neuronal networks are established in a nonoptimal manner. Inadequate neurotrophic support in adult individuals could ultimately be an underlying mechanism leading to decreased capacity of brain to adaptive changes and increased vulnerability to neurotoxic damage. Brain-derived neurotrophic factor (BDNF) is a mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system (CNS). In this review, we summarize findings regarding altered BDNF in schizophrenia and depression and animal models, as well as the effects of antipsychotic and antidepressive treatments on the expression of BDNF.
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PMID:BDNF in schizophrenia, depression and corresponding animal models. 1565 62

Brain-derived neurotrophic factor (BDNF) is a member of the structurally and functionally homologous neurotrophin family. It is the most widely distributed trophic factor in the brain, and participates in neuronal growth, maintenance, and use-dependent plasticity mechanisms such as long-term potentiation and learning. There are several lines of evidence supporting a role for BDNF in the treatment of depression. This paper reviews the neurotrophin hypothesis of antidepressant action, and examines our current understanding of activity-dependent mechanisms of BDNF expression and function in limbic regions of the brain. Our discussion starts with the original observations of monoaminergic neurotransmitter dysfunction that served as the basis for early antidepressant drug development, and outlines evidence for neurodegeneration and functional deficits existing with chronic stress and depression. We continue with evidence that enhancement in neurotrophic support and associated augmentation in synaptic plasticity and function may form the basis for antidepressant efficacy, and serve as a current and future focus in the quest for more rapid-acting and effective medication treatments. Finally, we follow the current search for the intracellular mechanisms of antidepressant interventions that may bring the monoaminergic and neurotrophic hypotheses together, and help us to more fully understand the roles of both neurotransmitter and growth factor. Principal challenges to the neurotrophin hypothesis, and inconsistencies between clinical and preclinical research results, are also pointed out, as these also guide future experiments that will refine our understanding of treatment mechanisms.
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PMID:Brain-derived neurotrophic factor and antidepressant activity. 1589 58

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT)n microsatellite, Val66Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val66Met polymorphism demonstrated significant overtransmission of the val allele (chi2=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val66Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val66Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.
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PMID:Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample. 1594 Feb 99

Chronic pain induces plastic changes in nociceptive sensory pathways, and is often accompanied and exacerbated by depression. Estrogen can influence nociceptive sensory processing, but the molecular mechanisms underlying sex differences in pain remain unclear. Brain-derived neurotrophic factor (BDNF) may orchestrate changes occurring during persistent pain or depression by increasing spinal nociceptive signaling and altering neuronal growth in higher brain structures. This study addressed whether estrogen regulates BDNF gene expression in central systems associated with nociceptive processing and/or affective state, which may in turn influence sex differences in pain sensitivity. Thus, BDNF gene expression was quantified in intact female rats in proestrus and diestrus, and in ovariectomized (OVX) rats with or without 17beta-estradiol (E2) replacement following intraplantar injection of dilute formalin as an inflammatory nociceptive stimulus. Twenty-four hours after formalin injection, central nervous system (CNS) tissues were removed and solution hybridization-nuclease protection assays used to quantify BDNF mRNA levels. Results demonstrated that estrogen replacement increased BDNF mRNA levels in the hippocampus, cortex and spinal cord. Cortical BDNF mRNA levels were significantly decreased by nociception, in the hippocampus this decrease was only evident in estrogen-treated rats. Spinal BDNF expression was robustly increased by nociception. The pain-evoked up-regulation of spinal BDNF gene expression was significantly potentiated by concomitant estrogen treatment. Results demonstrate that BDNF gene expression in certain brain structures is inhibited by inflammatory pain, yet estrogen may enhance central nervous system sensitization associated with sensory processing. Since alterations in BDNF gene expression in higher brain centers may be relevant to cognitive changes that occur in recurrent depression, these results may provide insights into the coincidence of chronic pain and depression.
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PMID:Estrogen increases nociception-evoked brain-derived neurotrophic factor gene expression in the female rat. 1602 Sep 28

Daily restraint for 3 weeks was shown to atrophy dendrites of hippocampal pyramidal neurons in rats. Brain-derived neurotrophic factor (BDNF), which maintains neuronal survival and morphology, has been shown to decrease in response to acute stress. Plasma glucocorticoid (GC) and serotonergic projections from the raphe nuclei play major roles in reducing BDNF synthesis in the hippocampus. We investigated BDNF mRNA levels there, together with plasma GC levels, GC receptors in the hippocampus/hypothalamus and 5-HT synthesizing enzyme, tryptophan hydroxylase in the raphe nuclei, in animals chronically stressed for 1-3 weeks, using in situ hybridization and immunohistochemistry. In these animals, BDNF mRNA levels were significantly decreased in the hippocampus after 6 h of restraint, but the ability of restraint to reduce BDNF synthesis seemed less robust than that seen in acute stress models. HPA axis response to stress in these animals assessed by plasma GC levels was delayed and sustained, and the GC receptor in the paraventricular hypothalamic nucleus was increased at 1 week. Tryptophan hydroxylase immunoreactivity was increased in the median raphe nucleus at 2-3 weeks. Repetitive stress-induced reduction of BDNF may partly contribute to the neuronal atrophy/death and reduction of hippocampal volume observed both in animals and humans suffering chronic stress and/or depression.
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PMID:Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. 1602 25


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