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: 5.26). 08/2008; 11(8):1047-61. DOI: 10.1017/S1461145708009000
Source: PubMed

ABSTRACT 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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    • "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 · 2.87 Impact Factor
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    • "This neurotrophin is found throughout the brain and is particularly abundant in the hippocampus and cerebral cortex, areas thought to be critical for the control of mood, emotion, and cognition (Ernfors et al., 1990). A morphological study has shown that BDNF protein and mRNA expression, as well as that of its receptor, tyrosine kinase B (TrkB), are significantly decreased in the prefrontal cortex (PFC) and hippocampus of suicide victims compared to control subjects (Pandey et al., 2008). Furthermore, BDNF is also decreased in the PFC and hippocampus in an animal model of mania induced by dextroamphetamine (Frey et al., 2006). "
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    ABSTRACT: The exposure to adverse events early in life may affect brain development. Omega-3 polyunsaturated fatty acid (n-3 PUFA) deficiency has been linked to the development of mood and anxiety disorders. The aim of this study was to examine the interaction between variations in the early environment (handling or maternal separation) and the chronic exposure to a nutritional n-3 PUFA deficiency on locomotor activity, sucrose preference, forced swimming test and on serum and hippocampal brain-derived neurotrophic factor (BDNF) levels. Rats were randomized into Non-handled (NH), Neonatal Handled (H) and Maternal Separated (MS) groups. Pups were removed from their dams (incubator at 32°C on postnatal days (PND) 1-10) during 10minutes/day (H) or 3hours/day (MS). On PND 35, males were subdivided into diets adequate or deficient in n-3 PUFA for 15weeks. H and MS gained weight differently, and animals receiving the n-3 PUFA deficient diet gained less weight. MS displayed a higher food consumption and higher consumption of sucrose solution during the secondhour of exposure to the sucrose preference test. No differences were observed in the swimming test. H group had increased locomotion and showed a higher response to amfepramone. No significant effect was observed on serum BDNF levels. BDNF protein levels were decreased in animals receiving the n-3 PUFA deficient diet. We observed that early life environment and a mild n-3 PUFA deficiency are able to affect several behavioral aspects (food and sucrose consumption and locomotor response), and lead to a differential hippocampal BDNF metabolism in adult life.
    Pharmacology Biochemistry and Behavior 03/2013; 107. DOI:10.1016/j.pbb.2013.03.006 · 2.82 Impact Factor
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    • "Patients frequently demonstrate sub-threshold symptoms with persistent cognitive impairment and functional decline (Goldstein et al., 2009). A morphological study has shown that protein and mRNA expression of BDNF and its receptor, tyrosine kinase B (TrkB), are significantly decreased in the prefrontal cortex (PFC) and hippocampus of suicide victims compared to control subjects (Pandey et al., 2008). Further, BDNF is also decreased in the PFC and hippocampus in an animal model of mania established using D-amphetamine (Frey et al., 2006). "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) plays a central role in synaptic plasticity and neurogenesis. Bipolar disorder (BD) is among the most disabling of all psychiatric disorders and is associated with poor outcomes. Some studies suggest that BDNF levels decrease during mood states and remain normal during euthymia, but other studies have contradicted this paradigm. Therefore, the aim of this study was to perform a meta-analysis of all studies that measured peripheral BDNF levels in adults with BD. We conducted a systematic review using electronic databases. Inclusion criteria were studies that measured BDNF in plasma or serum in vivo in adult patients with BD. The resulting studies were compiled to measure the effect sizes (ESs) of the differences in BDNF levels between BD patients in different mood states and controls. Thirteen studies were included with a total of 1113 subjects. The BDNF levels were decreased in both mania and depression when compared to controls (ES -0.81, 95% CI -1.11 to -0.52, p < 0.0001 and ES -0.97, 95% CI -1.79 to -0.51, p = 0.02, respectively). The BDNF levels were not different in euthymia when compared to controls (ES -0.20, 95% CI -0.61 to 0.21, p = 0.33). Meta-regression analyses in euthymia showed that age (p < 0.0001) and length of illness (p = 0.04) influenced the variation in ES. There was also an increase in BDNF levels following the treatment for acute mania (ES -0.63, 95% CI -1.11 to -0.15, p = 0.01). In conclusion, BDNF levels are consistently reduced during manic and depressive episodes and recover after treatment for acute mania. In euthymia, BDNF decreases with age and length of illness. These data suggest that peripheral BDNF could be used as a biomarker of mood states and disease progression for BD.
    Journal of Psychiatric Research 05/2011; 45(8):995-1004. DOI:10.1016/j.jpsychires.2011.03.002 · 4.09 Impact Factor
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