Different stress-related gene expression in depression and suicide
Introduction
Both depression and suicide are characterized by alterations in the stress response (Bao et al., 2008, Pandey, 2013) and by complex patterns of alterations in various brain regions and neurotransmitter systems (Gross-Isseroff et al., 1998). Different lines of investigation indicate the involvement of the prefrontal cortex (PFC) in depression, a brain region involved in, among other things, behavioral inhibition and impulse control. There is also a negative correlation between the severity of post-stroke depression and the distance between the brain injury site and the frontal pole (Narushima et al., 2003). Imaging studies have shown altered gray matter volume and thickness, and glucose metabolism and blood flow in the dorsolateral PFC (DLPFC) and anterior cingulate cortex (ACC) of depressed patients (Drevets et al., 2008). Furthermore, morphological studies have shown reduced neuronal and glia cell densities in both the DLPFC and ACC in depression (Cotter et al., 2001, Rajkowska et al., 1999). These alterations in the PFC may contribute to a number of signs and symptoms of depression, such as cognitive decline, negative self-evaluation, and suicidal tendencies (Elliott et al., 2011). Concerning neurochemical alterations, monoaminergic receptors and their transporters (serotonin, norepinephrine and dopamine) (Arranz et al., 1994, Mann, 2003, Shelton et al., 2009) and corticotropin-releasing hormone (CRH) in the hypothalamus: they have been frequently studied in relation to depression and suicide (Jokinen and Nordstrom, 2009, Wang et al., 2008), both of which are closely related to (regulation of) the stress response (Bao et al., 2008). In addition, CRH neurons are also located in most regions of the PFC (Swanson et al., 1983) that are part of the circuitry involved in modulating corticotropine, adrenocorticotroop hormone or cortisol-mediated responsivity to stress (Diorio et al., 1993). Also other neurotransmitters, such as the nitric oxide (NO) system, have drawn a lot of interest due to their changes in depression and suicide (Gao et al., 2013, Xing et al., 2002). 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).
However, there is still no agreement on a particular molecular ‘signature’, which allows for distinguishing expression changes in depression per se from depression with suicide. One problem that affects the interpretation of post-mortem studies on this topic is the occurrence of suicide in many of the depression cohorts reported in literature. For instance, postmortem studies that claimed to have determined molecular alterations in relation to depression had in fact selected, in the diagnosis group, depressed patients who (nearly) all committed suicide, and compared them with control subjects without any psychiatric disorder and who did not commit suicide (Bernard et al., 2011, Cotter et al., 2001, Dwivedi et al., 2006b, Martins-de-Souza et al., 2012, Rajkowska et al., 1999, Shelton et al., 2009). Vice versa, the studies focused on suicide appeared to compare suicide cases to matched controls without any psychiatric disorder (Dwivedi et al., 2006a, Dwivedi et al., 2006b, Poulter et al., 2008, Thalmeier et al., 2008). Such methodological aspects have so far made it impossible to distinguish neurochemical alterations due to depression per se from those due to suicide.
We therefore investigated whether a series of stress-related candidate molecules differ in their expression in depressed patients in relation to suicide. We studied a Stanley Medical Research Institute (SMRI) patient cohort consisting of three groups: major depressive disorder patients who committed suicide (MDD-S), MDD patients who died of non-suicidal causes (MDD-NS), and control subjects without a psychiatric disorder, to answer the question whether suicide is responsible for the altered gene expression. In addition, elderly depressed patients who did not commit suicide (DEP) and their matched controls from the Netherlands Brain Bank (NBB) were studied to see what the alterations related to depression were, confirming the findings about young MDD-NS from SMRI in elderly depressed non-suicide patients.
Section snippets
Subjects from the Stanley Medical Research Institute (SMRI)
All patients whose brain material was obtained from SMRI had given permission for a brain autopsy and for the use of their brain material and clinical data for research purposes. MDD diagnoses were based on the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and were made independently by two senior psychiatrists based on medical records and, when necessary, telephone interviews with family members. This systematized procedure was carried out as described before (Torrey et al.,
Altered mRNA expression levels in suicide and depression
In the ACC of SMRI patients, CRH transcripts were up-regulated in the MDD-S patients and compared to MDD-NS patients (1.98 fold changes, P = 0.003) and to the control group (1.56 fold changes, P = 0.008), while no differences were observed between MDD-NS patients and control subjects (P = 0.405) (Fig. 1A). In the DLPFC, we could not find any significant differences between MDD-S, MDD-NS, and control subjects (P = 0.487, Fig. 1B). In the NBB cohort, there was no significant change in CRH
Discussion
In an attempt to understand the biological processes associated with depression and suicide, one approach has been to study molecular changes in brain tissue obtained from patients that suffered from these disorders. So far, many post-mortem studies have searched for candidate genes, but there is considerable inconsistency in the reported results, which limits our understanding of the pathophysiology of these disorders. We show here that the composition of cohorts, i.e. the proportion of
Role of funding source
This investigation was supported by the projects of the Royal Netherlands Academy of Arts and Sciences (10CDP037), Nature Science Foundation of Zhejiang Province (LY12H09007), Nature Science Foundation of China (31271130), Major Research Projects of Nature Science Foundation of China (91332102).
Contributors
J. Zhao, W. Kamphuis, and D. Swaab designed the protocol. J. Zhao, X.-R. Qi, S.-F. Gao, J. Lu and D.J. van Wamelen undertook data collection. J. Zhao, W. Kamphuis and A.-M. Bao undertook statistical analysis, and J. Zhao wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
None to declare.
Acknowledgments
Postmortem brain tissue was donated by The Stanley Medical Research Institute Brain Collection and Netherlands Brain Bank. We are indebted to them for providing us with the brain material and patient information. We thank Dr. Ronald WH Verwer for statistical assistance, Arja A Sluiter for her technical advice, and Wilma Verweij for secretarial help.
References (53)
- et al.
Brain 5-HT1A, 5-HT1D, and 5-HT2 receptors in suicide victims
Biol. Psychiatry
(1994) - et al.
The stress system in depression and neurodegeneration: focus on the human hypothalamus
Brain Res. Rev.
(2008) - et al.
Autoradiographic analysis of serotonin 5-HT1A receptor binding in the human brain postmortem: effects of age and alcohol
Brain Res.
(1991) - et al.
The suicide brain: a review of postmortem receptor/transporter binding studies
Neurosci. Biobehav. Rev.
(1998) Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy
J. Affect Disord.
(2001)- et al.
HPA axis hyperactivity and attempted suicide in young adult mood disorder inpatients
J. Affect Disord.
(2009) - et al.
Chronic stress is linked to 5-HT(1A) receptor changes and functional disintegration of the limbic networks
Neuroimage
(2011) - et al.
5-HT1A receptor binding sites in post-mortem brain samples from depressed suicides and controls
J. Affect Disord.
(1997) - et al.
Gene environment interaction studies in depression and suicidal behavior: an update
Neurosci. Biobehav. Rev.
(2013) - et al.
Stress and glucocorticoids regulated corticotropin releasing factor in rat prefrontal cortex
Mol. Cell. Endocrinol.
(2011)
Brain serotonin 1A receptor binding as a predictor of treatment outcome in major depressive disorder
Biol. Psychiatry
Apparent absence of aging and gender effects on serotonin 1A receptors in human neocortex and hippocampus
Brain Res.
GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes
Biol. Psychiatry
Aberrant stress hormone receptor balance in the human prefrontal cortex and hypothalamic paraventricular nucleus of depressed patients
Psychoneuroendocrinology
Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression
Biol. Psychiatry
5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants
Neuron
Lasting epigenetic influence of early-life adversity on the BDNF gene
Biol. Psychiatry
NIDD, a novel DHHC-containing protein, targets neuronal nitric-oxide synthase (nNOS) to the synaptic membrane through a PDZ-dependent interaction and regulates nNOS activity
J. Biol. Chem.
Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A
Neuroscience
Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET
Neuropsychopharmacology
The stanley foundation brain collection and neuropathology consortium
Schizophr. Res.
Decreased calcium-dependent constitutive nitric oxide synthase (cNOS) activity in prefrontal cortex in schizophrenia and depression
Schizophr. Res.
Gene expression of GABA and glutamate pathway markers in the prefrontal cortex of non-suicidal elderly depressed patients
J. Affect Disord.
Postmortem findings in suicide victims. Implications for in vivo imaging studies
Ann. N. Y. Acad. Sci.
Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression
Mol. Psychiatry
Hypothalamic-pituitary-adrenal axis dysfunction as a neurobiological correlate of emotion dysregulation in adolescent suicide
World J. Pediatr.
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2020, Advances in Clinical ChemistryCitation Excerpt :Furthermore, a strong relationship between HPA axis dysfunction and suicide has been highlighted, although in some studies this association has not been weighted for the presence or severity of MDD [50]. Postmortem studies comparing subjects who died by suicide than controls who died for other causes have shown higher adrenal weight [51], elevated CRH levels in brainstem and CSF as well as lower mRNA CRH1 receptor levels in the frontal cortex [52]. Moreover, decrease of GR protein expression has been found in PFC and amygdala of postmortem brains of adolescent suicide victims compared with controls [53].