Research reportNeurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs
Introduction
In modern societies, suicide represents a major public health problem, but our current knowledge of the neurobiological factors of risk is still poor. A number of reports pointed out that affective illness and stress could be major factors in suicidal behavior, and several studies have reported biochemical changes in postmortem brains [24], [25], [35].
Compelling evidence has reported alterations in the serotoninergic system in the patients who committed suicide or suicide attempts [18], [24]. Such findings have led to the hypothesis that reduced 5 HT activity is associated with increased risk of suicide [14], [18], [25], [27]. However, the exact pathway and the mechanism of dysfunction have not been fully examined. Recent studies have reported anatomical changes, including neuronal atrophy or cell death in the limbic system of patients with mood disorders [34]. Brain imaging studies have reported changes in volume of hippocampus and prefrontal cortex in depressed patients with major depression, post-traumatic stress disorder or bipolar disorder [6], [9]. These data are consistent with the possibility of reduced neurotrophic support or synaptic remodeling in depression. Alternatively, neuroimaging studies have indicated that patients with a history of suicide attempts have abnormal MRI findings, probably because of a disruption of the critical neuroanatomical pathways [1]. Given the significance of neurotrophic factors such as the brain-derived neurotrophic factor (BDNF) and the neurotrophin-3 (NT-3) in neuronal plasticity and in stress and affective disorders [10], [33], it appears reasonable to suggest that neurotrophins may represent an appropriate candidates for studies of suicide victims. These neurotrophins are structurally related members of the nerve growth factor (NGF) family of neurotrophic factors (including NGF, BDNF, NT-3, and NT-4/5) which play key roles in neuronal survival, differentiation, connectivity, and plasticity during development and adulthood [16], [29].
The link between 5 HT system and BDNF expression or function has been established [23], [26]. BDNF is one of the major downstream targets of serotonin signaling [26] and inversely, it was shown to increase 5 HT innervation [23]. Several studies have demonstrated that stress can decrease the expression of BDNF, while long-term administration of antidepressant drugs (AD) and electroconvulsive therapy can increase it [2], [33]. When administered to stressed animals, BDNF was shown to produce antidepressant effect by antagonizing behavioral models of depression [30], [31].
In parallel, human studies have provided data that support the roles played by BDNF and NT-3 in the pathophysiology of stress and major depression [19], [33] and in the action of AD drugs [7], [8]. This role of neurotrophins in affective disorders has been strengthened by genetic studies which reported for either BDNF or its low-affinity receptor, p75, gene polymorphisms associated to depressive disorder and attempted suicide [21], [32].
The present investigation was undertaken to examine whether there is an abnormality in the brain BDNF and NT-3 protein levels and whether the abnormality is related only to major depression. Groups of suicide victims with either major depression or other psychiatric disorders were identified and compared to non-psychiatric non-suicide controls. Further, to elucidate whether the neurotrophins might be affected by psychotropic drugs, drug-treated suicide victims were compared to drug-free controls. The present study provides novel evidence of the role played by neurotrophins (BDNF and NT-3) in pathophysiology of suicide, both in major depression and other diagnosis, and suggests that neurotrophins may serve as drug mediators.
Section snippets
Postmortem brain samples
Human brains were collected at autopsy from the Institute of Forensic Medicine, Geneva, Switzerland. This study was approved by the Research and Ethics Review Board of the department of Psychiatry, Faculty of Medecine in Geneva. This collection was obtained following legal procedures by the République et Canton de Genève, which, in some cases, requires family consent.
After the brain was removed from the cranium, it was examined for neuropathologic abnormalities and then three brain areas were
Results
Fig. 1 displays representative Western blots of immunolabeling of BDNF (Fig. 1a) and β-actin (Fig. 1b) bands for one subject of each group. The bands of BDNF and β-actin were located at 14 kDa and 46 kDa, respectively. The BDNF's identity was validated by the use of BDNF antigenic-peptide which suppress the 14 kDa but not the 46 kDa (Fig. 1c). In Fig. 1d, an assay of increasing protein levels performed to determine the linear range is displayed. In general, 25–50 μg prot were routinely used and
Discussion
Recent studies on the neurobiology of suicide have indicated that, in addition to altered serotoninergic system, subjects can manifest changes on cellular and structural level in discrete brain nuclei of the limbic system [1]. Given the importance of neurotrophins in cell survival and neuroplasticity, this study was undertaken to detect some association of BDNF/NT-3 and suicide.
The study has found a significant decrease of BDNF levels both in hippocampus and ventral prefrontal cortex, but not
Acknowledgments
This study was partly supported by grant No 3200BO-102168 from the National Suiss Fund for Scientific Research (Pr Alain Malafosse). The authors are grateful to the staff of the Institute of Forensic Medicine (CMU) and the technicians of the Service of Neuropsychiatry (HUG).
References (37)
- et al.
MRI correlates of suicide attempt history in unipolar depression
Biol. Psychiatry
(2001) - et al.
Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain
Biol. Psychiatry
(2003) - et al.
Localized alterations in pre- and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims
Brain Res.
(1995) - et al.
Morphometric studies of the entorhinal cortex in neuropsychiatric patients and controls: clusters of heterotopically displaced lamina II neurons are not indicative of schizophrenia
Schizophr. Res.
(1998) - et al.
Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication
Biol. Psychiatry
(2001) - et al.
Brain-derived neurotrophic factor and neurotrophin-3 levels in Alzheimer's disease brains
Int. J. Dev. Neurosci.
(2000) - et al.
Entorhinal cortex regulation of multiple brain-derived neurotrophic factor promoters in the rat hippocampus
Neuroscience
(1993) - et al.
Decreased serum brain-derived neurotrophic factor levels in major depressed patients
Psychiatry Res.
(2002) - et al.
The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system
Neuropsychopharmacology
(2001) - et al.
The neurotrophin hypothesis for synaptic plasticity
Trends Neurosci.
(2000)
Antidepressant-like effect of brain-derived neurotrophic factor (BDNF)
Pharmacol. Biochem. Behav.
The anatomy of mood disorders—review of structural imaging studies
Biol. Psychiatry
The prisoners of despair: right hemisphere deficiency and suicide
Neurosci. Biobehav. Rev.
Emotion, decision making and the orbitofrontal cortex
Cereb. Cortex
Hippocampal volume reduction in major depression
Am. J. Psychiatry
Neurotrophins as mediators of drug effect on mood, addiction, and neuroprotection
Mol. Neurobiol.
Subgenual prefrontal cortex abnormalities in mood disorders
Nature
Role of neurotrophic factors in the etiology and treatment of mood disorders
Neuromol. Med.
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