Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims
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.
- SourceAvailable from: Terence Y Pang[Show abstract] [Hide abstract]
ABSTRACT: There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer's, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies.Frontiers in Psychiatry 03/2015; 6:32. DOI:10.3389/fpsyt.2015.00032
- [Show abstract] [Hide abstract]
ABSTRACT: Objectives. Suicide is a serious public health concern, and it is partly genetic. The brain-derived neurotrophic factor (BDNF) gene has been a strong candidate in genetic studies of suicide (Dwivedi et al., Arch Gen Psychiatry 2010;60:804-815; Zai et al., Prog Neuropsychopharmacol Biol Psychiatry 2012;34:1412-1418) and BDNF regulates the expression of the dopamine D3 receptor. Objective. We examined the role of the BDNF and DRD3 genes in suicide. Methods. We analysed four tag single-nucleotide polymorphisms (SNPs) in BDNF and 15 SNPs in the D3 receptor gene DRD3 for possible association with suicide attempt history in our Canadian sample of Schizophrenia (SCZ) patients of European ancestry (N = 188). Results. In this sample, we found a possible interaction between the BDNF Val66Met and DRD3 Ser9Gly SNPs in increasing the risk of suicide attempt(s) in our SCZ sample. Specifically, a larger proportion of SCZ patients who were carrying at least one copy of the minor allele at each of the Val66Met and Ser9Gly functional markers have attempted suicides compared to patients with other genotypes (Bonferroni P < 0.05). However, we could not replicate this finding in samples from other psychiatric populations. Conclusions. Taken together, the results from the present study suggest that an interaction between BDNF and DRD3 may not play a major role in the risk for suicide attempt, though further studies, especially in SCZ, are required.The World Journal of Biological Psychiatry 09/2014; 16(3):1-9. DOI:10.3109/15622975.2014.953011 · 4.23 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Magnetization transfer imaging (MTI) provides a quantitative measure of the macromolecular structural integrity of brain tissue, as represented by magnetization transfer ratio (MTR). In this study, we utilized MTI to identify biophysical alterations in MDD patients with a history of suicide attempts relative to MDD patients without such history. The participants were 36 medication-free MDD patients, with (N = 17) and without (N = 19) a history of a suicide attempt, and 28 healthy controls matched for age and gender. Whole brain voxel-based analysis was used to compare MTR across three groups and to analyze correlations with symptom severity and illness duration. We identified decreased MTR in left inferior parietal lobule and right superior parietal lobule in suicide attempters relative to both non-attempters and controls. Non-attempters also showed significantly reduced MTR in left inferior parietal lobule relative to controls, as well as an MTR reduction in left cerebellum. These abnormalities were not correlated with symptom severity or illness duration. Depressed patients with a history of suicide attempt showed bilateral abnormalities in parietal cortex compared to nonsuicidal depressed patients and healthy controls. Parietal lobe abnormalities might cause attentional dysfunction and impaired decision making to increase risk for suicidal behavior in MDD.Scientific Reports 04/2015; 5:9670. DOI:10.1038/srep09670 · 5.08 Impact Factor