Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims

Department of Psychiatry, University of Illinois at Chicago, College of Medicine, Chicago, IL, USA.
The International Journal of Neuropsychopharmacology (Impact Factor: 4.01). 08/2008; 11(8):1047-61. DOI: 10.1017/S1461145708009000
Source: PubMed


Teenage suicide is a major public health concern, but its neurobiology is not very well understood. Stress and major mental disorders are major risk factors for suicidal behaviour, and it has been shown that brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) are not only regulated by stress but are also altered in these illnesses. We therefore examined if BDNF/TrkB signalling is altered in the post-mortem brain of teenage suicide victims. Protein and mRNA expression of BDNF and of TrkB receptors were determined in the prefrontal cortex (PFC), Brodmann's Area 9 (BA 9), and hippocampus obtained from 29 teenage suicide victims and 25 matched normal control subjects. Protein expression was determined using the Western blot technique; mRNA levels by a quantitative RT-PCR technique. The protein expression of BDNF was significantly decreased in the PFC of teenage suicide victims compared with normal control subjects, whereas no change was observed in the hippocampus. Protein expression of TrkB full-length receptors was significantly decreased in both PFC and hippocampus of teenage suicide victims without any significant changes in the truncated form of TrkB receptors. mRNA expression of both BDNF and TrkB was significantly decreased in the PFC and hippocampus of teenage suicide victims compared with normal control subjects. These studies indicate a down-regulation of both BDNF and its receptor TrkB in the PFC and hippocampus of teenage suicide victims, which suggests that stress and altered BDNF may represent a major vulnerability factor in teenage suicidal behaviour.

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Available from: Robert R Conley, Aug 31, 2015
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    • "Retinoid signaling, brain-derived neurotropic factor (BDNF) and the gene that encodes its high-affinity receptor, tropomycin kinase B (TrkB), have received considerable attention in human studies of suicidal behavior. Some of these studies have revealed that people who commit suicide have decreased mRNA and/or protein levels of BDNF, TrkB, or both, in the PFC (Ernst et al., 2009; Maussion et al., 2014; Pandey et al., 2008). Their decreased expression correlated with hypermethylation of the BDNF promoters in exons 4 and 9 (Roth et al., 2009). "
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    ABSTRACT: Suicide occurs in some, but not all depressed patients. So far, it remains unknown whether the studied stress-related candidate genes change in depression, suicide or both. The prefrontal cortex (PFC) is involved in, among other things, impulse control and inhibitory behavior and plays an important role in both suicide and depression. We have employed qPCR to study 124 anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC) brain samples, obtained from two brain banks, from: i) young depressed patients (average age 43 years) who committed suicide (MDD-S) and depressed patients who died from causes other than suicide (MDD-NS) and from ii) elderly depressed patients (average age 75 years) who did not commit suicide (DEP). Both cohorts were individually matched with non-psychiatric non-suicide control subjects. We determined the transcript levels of hypothalamic-pituitary-adrenal axis-regulating molecules (corticotropin-releasing hormone (CRH), CRH receptors, CRH binding protein, mineralocorticoid receptor/glucocorticoid receptor), transcription factors that regulate CRH expression, CRH-stimulating cytokines, chaperone proteins, retinoid signaling, brain-derived neurotrophic factor and tropomyosin-related kinase B, cytochrome proteins, nitric oxide synthase (NOS) and monoamines. In the MDD-S group, expression levels of CRH and neuronal NOS-interacting DHHC domain-containing protein with dendritic mRNA (NIDD) were increased. Other changes were only present in the DEP group, i.e. decreased NIDD, and increased and 5-hydroxytryptamine receptor 1A (5-HT1A) expression levels. Changes were found to be more pronounced in the anterior cingulate cortex than in the dorsolateral PFC. Depressed patients who committed suicide have different gene expression patterns than depressed patients who died of causes other than suicide. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Psychiatric Research 09/2015; 68:176-185. DOI:10.1016/j.jpsychires.2015.06.010 · 3.96 Impact Factor
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    • "Immunolabeling and mRNA levels of TrkA and TrkC were decreased in the hippocampus of suicide subjects with major depression when compared to normal subjects and p75NTR was increased [32]. In post-mortem brain of teenage suicide victims TrkB mRNA levels were decreased in both prefrontal cortex and hippocampus [33]. "
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    ABSTRACT: Epilepsy and psychiatric comorbidities are frequently associated, but their common biological substrate is unknown. We have previously reported altered structural elements and neurotrophins (NTs) expression in mesial temporal lobe epilepsy (MTLE) patients with psychiatric comorbidities. NTs receptors can regulate neurotransmission and promote neuroplasticity, being important candidates in the regulation and manifestation of psychopatological states and seizure-related events. MTLE hippocampi of subjects without psychiatric history, MTLE¿+¿major depression, MTLE¿+¿interictal psychosis derived from epilepsy surgery, and control necropsies were investigated for p75NTR, TrkB, TrkA, and TrkC immunohistochemistry. Increased expression of p75NTR, decreased TrkA, unaltered TrkC, and complex alterations involving TrkB expression were seen in MTLE groups. Increased TrkB expression in patients without complete seizure remission and in those with secondarily generalized seizures was seen. Decreased p75NTR expression associated with interictal psychosis, and increased TrkB in those with psychosis or major depression was also reported, although their p75NTR/TrkB ratios were lower than in MTLE without psychiatric comorbidities. Our results provide evidence of alterations in expression of NTs receptors in the epileptogenic hippocampus that are differentially modulated in presence of psychiatric comorbidities. As already explored in animal models, even in chronic human MTLE increased TrkB expression, among other NT receptors alterations, may play a major role in seizure type, frequency and surgery outcome.
    07/2014; 2(1):81. DOI:10.1186/PREACCEPT-5185032491303487
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    • "In addition, the MEK/ERK pathway contributes to the neuroprotection provided by BDNF against glutamate-induced neuronal cell death (Almeida et al. 2005), and a recent study demonstrated that BDNF/TrkB signaling increases the transcription of GAD1 through a MAPK-dependent manner in cortical GABAergic interneurons (Sanchez-Huertas and Rico 2011). Moreover, Previous human postmortem brain studies demonstrated that BDNF and TrkB levels are decreased in dlPFC (BA 9) of teenage suicide victims (Pandey et al. 2008) and subjects with MDD (Dwivedi et al. 2003). Although this study suggests some interesting avenues into the possible linkage between the reduced levels of SLC1A2 and GAD1 in dlPFC in MDD, we believe that it should be viewed at this stage as exploratory. "
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    ABSTRACT: Previous human postmortem studies have shown that expression of glutamate transporters (SLC1A2 and SLC1A3) and gamma-aminobutyric acid-synthesizing enzyme [glutamic acid decarboxylase 1 (GAD1)] are reduced in the dorsolateral prefrontal cortex (dlPFC) in subjects with major depressive disorder (MDD). However, no studies have explored the association between these two molecules and its related biological processes in MDD because of limited postmortem sample availability. Data sharing using the Stanley neuropathology consortium integrative database (SNCID), a web-based tool that integrates datasets from the same postmortem brain samples, allowed us to reanalyze existing postmortem data efficiently. We found two datasets where the mRNA levels of GAD1 and SLC1A2 in subregions of the dlPFC were significantly and marginally lower in subjects with MDD (n = 15) than in controls (n = 15) (p = 0.045 and 0.057, respectively). In addition, there was a positive correlation between these two molecules (n = 30, p < 0.05). Spearman's rank correlation analysis using all available datasets revealed that the expression levels of both GAD1 and SLC1A2 mRNAs were commonly correlated with the expression levels of several neuropathological markers in the dlPFC in all of the SNCID subjects (n = 60, p < 0.001). Most of these markers are known to be involved in the RAF/MEK/ERK signal transduction pathway. This exploratory study provides an initial step for future studies to investigate an association between the reductions in SLC1A2 and GAD1 mRNA expression and their relation to the attenuation of the RAF/MEK/ERK signaling pathway in the dlPFC in MDD. The integration of the existing archival data may shed light on one important aspect of the pathophysiology of MDD.
    Journal of Neural Transmission 03/2014; 121(7). DOI:10.1007/s00702-014-1189-z · 2.40 Impact Factor
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