Reduced Neuropeptide Y Concentrations in Suicide Brain

Neuropeptide Y (NPY) was measured in postmortem brain tissue from victims of suicide and from individuals dying a sudden natural or accidental death (controls). Concentrations of NPY-immunoreactivity were measured by radioimmunoassay in frontal cortex (BA 10), temporal cortex (BA 22), caudate nucleus, and cerebellum. Concentrations of NPY-immunoreactivity were significantly lower in postmortem frontal cortex (-14%) and caudate nucleus (-27%) from suicide victims compared with age-matched controls. A subgroup of suicides with evidence of a history of depression revealed more robust reductions in concentrations of NPY-immunoreactivity in frontal cortex and caudate nucleus, as did four individuals who died from natural causes and also were described as having a possible history of depression. Concentrations of NPY-immunoreactivity in temporal cortex and cerebellum from victims of suicide or from the subgroup of subjects with a possible history of depression were not significantly different from those of age-matched controls. We suggest there is a deficit in the brain NPY system leading to region-specific reductions in peptide concentrations in subjects who have a history of depression.     

Autoradiographic Demonstration of Increased α2-Adrenoceptor Agonist Binding Sites in the Hippocampus and Frontal Cortex of Depressed Suicide Victims

Abstract: To examine directly in the brain the status of α₂-adrenoceptors in major depression, the specific binding of the agonist [³H]UK 14304 was measured by quantitative receptor autoradiography in the hippocampus and frontal cortex of suicide victims (n = 17) with a retrospective diagnosis of depression (n = 7) or other psychiatric disorders (n = 10) as well as of matched control subjects (n = 9). In suicide victims, a significant increase in the number of α₂-adrenoceptors was found in the CA1 field (40%) and dentate gyrus (20%) of the hippocampus and in the external layers I (33%) and II (31%) of the frontal cortex, compared with that in matched controls. In depressed suicide victims, the increase in α₂-adrenoceptors in the CA1 field (57%) was significantly greater (24%, p < 0.05) than that observed in the group of suicide victims with other diagnoses (26%). In the same depressed suicide victims, the increase in cortical α₂-adrenoceptors was restricted to layer I (34%) and it was equivalent to that found in layer I (33%) of suicide victims with other diagnoses. The results indicate that suicide is associated with increases in the high-affinity state of brain α₂-adrenoceptors and that there is a pronounced localized increase of this inhibitory receptor in the hippocampus of depressed suicide victims.     

Normal levels of tryptophan hydroxylase immunoreactivity in the dorsal raphe of depressed suicide victims

A variety of evidence suggests that serotonin neurotransmission is altered in the brain of suicide victims and depressed patients. While numerous post-mortem studies have investigated serotonin transporters and receptors, few studies have examined the biosynthetic integrity of the rate-limiting enzyme, tryptophan hydroxylase (TPH), in post-mortem specimens of depressed suicide subjects. Therefore, the aim of the present study was to test the hypothesis that the levels of TPH immunoreactivity (IR) are altered in specific subnuclei of the dorsal raphe (DR) in depressed suicide victims. Suicide victims with a confirmed diagnosis of major depression were matched with non-psychiatric controls based on age, gender and post-mortem interval. Frozen tissue sections containing the DR were selected from two anatomical levels and processed for TPH radioimmunocytochemistry. The optical density corresponding to the regional levels of TPH-IR was quantified in specific subnuclei of the DR from the film autoradiographic images. No significant differences in the levels of TPH-IR were found in any DR subnuclei between depressed suicide victims and control subjects. The lack of change in TPH-IR levels does not necessarily imply that serotonin synthesis or neurotransmission is not altered in the brain of depressed subjects. Many factors influence and regulate serotonin synthesis, and it is conceivable that alterations exist at other levels of regulation of serotonin biosynthesis in depression. Our findings indicate that TPH biosynthesis, at least at the protein level, is not significantly altered in the DR of depressed suicide victims.     

Neuropeptide Y and natural killer cell activity: findings in depression and Alzheimer caregiver stress.

A reduction in immune function has been found in patients with a major depressive disorder and in persons undergoing severe life stress. This study investigated the association between increased sympathetic nervous system activity and reduced natural killer (NK) cytotoxicity in depression and Alzheimer caregiver stress. NK activity and plasma concentrations of epinephrine, norepinephrine, and neuropeptide Y were measured in depressed patients (n = 19) and age- and gender-matched controls (n = 19), and in Alzheimer spousal caregivers (n = 48) and matched noncaregiver controls (n = 17). Plasma levels of neuropeptide Y, but not circulating basal levels of catecholamines, were significantly (P less than 0.01) elevated in the depressed patients and in the caregivers compared with respective controls. NK activity was significantly (P less than 0.001) lower in the depressed patients than in their controls, but not different between the caregivers and the noncaregiver controls. Circulating concentrations of neuropeptide Y, but not catecholamines, were inversely correlated (r = -0.31, P less than 0.001) with NK activity. In addition, multiple regression analyses demonstrated that the significant (P less than 0.01) association between neuropeptide Y and natural cytotoxicity was independent of the relative contribution of age and basal and dynamic levels of epinephrine and norepinephrine. These findings suggest that increased sympathetic nervous system activity and the release of neuropeptide Y may be associated with the modulation of NK cytotoxicity.     

Influence of Region-Specific Alterations of Neuropeptidase Content on the Catabolic Fates of Neuropeptides in Alzheimer's Disease

Abstract: We established the cartography of 11 exo- and endopeptidases in the frontal and parietal cortices and in the cerebellum of brains of patients diagnosed with a senile dementia of the Alzheimer's type (SDAT). Comparison with those of four subjects who had died without known neurologic or psychiatric illness indicated that there existed a region-specific alteration of the peptidase contents in the disease. In the frontal area of SDAT brains, postproline dipeptidyl aminopeptidase and aminopeptidase M activities were significantly reduced. In the parietal cortex of SDAT brain, activities of three additional endopeptidases—angiotensin-converting enzyme, proline endopeptidase, and endopeptidase 24.15—were also drastically reduced. In contrast, the cerebellum displayed a set of proteolytic activities that remained unaffected in SDAT brain. The putative influence of the disease on the catabolic fates of neurotensin, neuropeptide Y, and somatostatin(1–14) was investigated. Neurotensin was catabolized at identical rates in the frontal and parietal cortices in nondemented and SDAT brains. In contrast, neuropeptide Y metabolism was slowed down in SDAT brains in the frontal but not in the parietal cortex. Finally, the degradation velocities of somatostatin(1–14) were lowered in both cortical areas of SDAT brains. It is interesting that, by means of specific peptidase inhibitors, we demonstrated that endopeptidase 24.15 participated in somatostatin(1–14) inactivation in the parietal but not in the frontal cortex. It is suggested that the lowering of the rate of somatostatin(1–14) inactivation in the parietal cortex of SDAT brains likely results from the depletion of endopeptidase 24.15 in this brain region.     

Reduced neuropeptide Y mRNA levels in the frontal cortex of people with schizophrenia and bipolar disorder

To study the change of gene expression in the brain tissues of schizophrenia, we used the gene expression monitoring technology and compared two sets of pools each containing four RNA samples of frontal cortex that were randomly selected from the control or schizophrenia group. We found that the expression of two genes were commonly altered in four pairwise comparisons; the expression of DEAD-box protein p72 (p72) gene was increased and neuropeptide Y (NPY) gene expression was decreased in the schizophrenia group compared with the control group. To substantiate these results, we estimated their mRNA levels by the real time TaqMan method in the 15 samples of each frontal or temporal cortex of four matched groups of schizophrenia, bipolar disorder, major depression and normal controls. A statistically significant decrease was observed for NPY in the frontal, but not in the temporal cortex, in the schizophrenia group (P=0.003). A decrease was also observed in the frontal cortex of the bipolar disorder group (P=0.031). In contrast, p72 gene expression showed no significant difference among the four groups. In conclusion, by novel technology of DNA array and TaqMan PCR analyses, we found that neuropeptide Y mRNA levels were significantly reduced in the frontal cortex in both schizophrenia and bipolar disorder.     

Up-Regulation of Immunolabeled α2A-Adrenoceptors, Gi Coupling Proteins, and Regulatory Receptor Kinases in the Prefrontal Cortex of Depressed Suicides

Abstract : Suicide and depression are associated with an increased density of α₂-adrenoceptors (radioligand receptor binding) in specific regions of the human brain. The function of these inhibitory receptors involves various regulatory proteins (G_i coupling proteins and G protein-coupled receptor kinases, GRKs), which work in concert with the receptors. In this study we quantitated in parallel the levels of immunolabeled α_2A-adrenoceptors and associated regulatory proteins in brains of suicide and depressed suicide victims. Specimens of the prefrontal cortex (Brodmann area 9) were collected from 51 suicide victims and 31 control subjects. Levels of α_2A-adrenoceptors, Gα_1/2 proteins, and GRK 2/3 were assessed by immunoblotting techniques by using specific polyclonal antisera and the immunoreactive proteins were quantitated by densitometry. Increased levels of α_2A-adrenoceptors (31-40%), Gα_1/2 proteins (42-63%), and membrane-associated GRK 2/3 (24-32%) were found in the prefrontal cortex of suicide victims and antidepressantfree depressed suicide victims. There were significant correlations between the levels of GRK 2/3 (dependent variable) and those of α_2A-adrenoceptors and Gα_1/2 proteins (independent variables) in the same brain samples of suicide victims (r = 0.56, p = 0.008) and depressed suicide victims (r = 0.54, p = 0.041). Antemortem antidepressant treatment was associated with a significant reduction in the levels of Gα_1/2 proteins (32%), but with modest decreases in the levels of α_2A-adrenoceptors (6%) and GRK 2/3 (18%) in brains of depressed suicide victims. The increased levels in concert of α_2A-adrenoceptors, Gα_1/2 proteins, and GRK 2/3 in brains of depressed suicide victims support the existence of supersensitive α_2A-adrenoceptors in subjects with major depression.     

Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase,phosphatidylinositol 3-kinase,Akt and mitogen-activated protein kinase

Positron emission tomography studies in major depression show reduced serotonin (5-HT)1A receptor antagonist-binding potentials in many brain regions including occipital cortex. The functional meaning of this observation in terms of signal transduction is unknown. We used postmortem brain samples from depressed suicide victims to examine the downstream effectors of 5-HT1A receptor activation. The diagnosis was established by means of psychological autopsy using Diagnostic and Statistical Manual of Mental Disorders (DSM) III-R criteria. Measurements of [35S]GTPgammaS binding to Galphai/o in the occipital cortex of suicide victims and matched controls revealed a blunted response in suicide subjects and a decrease in the coupling of 5-HT1A receptor to adenylyl cyclase. No significant group differences were detected in the expression levels of Galphai/o, Galphaq/11 or Galphas proteins, or in the activity of cAMP-dependent protein kinase A. Studies of a parallel transduction pathway downstream from 5-HT1A receptor activation demonstrated a decrease in the activity of phosphatidylinositol 3-kinase and its downstream effector Akt, as well as an increase in PTEN (phosphatase and tensin homolog deleted on chromosome 10), the phosphatase that hydrolyzes phosphatidylinositol 3,4,5-triphosphate. Finally, the activation of extracellular signal-regulated kinases 1 and 2 was attenuated in suicide victims. These data suggest that the alterations in agonist-stimulated 5-HT1A receptor activation in depressed suicide victims are also manifest downstream from the associated G protein, affecting the activity of second messengers in two 5-HT1A receptor transduction pathways that may have implications for cell survival.     

G Protein-Coupled Cyclic AMP Signaling in Postmortem Brain of Subjects with Mood Disorders

Components of cyclic AMP (cAMP) signaling were examined in postmortem cerebral cortex of a well characterized group of patients with mood disorders and nonpsychiatric control subjects. We measured G protein levels, adenylyl cyclase (AC) activity, and CREB levels in cerebral cortex of the subjects with respect to diagnosis, treatment, and suicide. There was no effect of diagnosis on any measure, except for a trend toward decreased stimulated AC activity in subjects with mood disorders relative to control subjects. We also detected a significant effect of suicide on temporal cortex CREB levels in subjects that died as a result of suicide relative to those that did not, which was more evident in patients with major depressive disorder. Bipolar disorder (BD) subjects treated with anticonvulsants at the time of death had decreased temporal cortex CREB levels relative to those not receiving anticonvulsants. Furthermore, we found a trend toward decreased occipital cortex G alpha(s) (short) levels in BD subjects treated with lithium. These results support the hypothesis of altered cAMP signaling in mood disorders and raise the possibility that factors other than diagnosis, such as treatment and suicide, may be relevant to cell-signaling abnormalities reported in the literature.     

The Impact of Improving Suicide Death Classification in South Korea: A Comparison with Japan and Hong Kong

IntroductionThe suicide rate of South Korea has increased dramatically during the past decades, as opposed to steadily decreasing trends in Japan and Hong Kong. Although the recent increase of suicide in South Korea may be related to changing socioeconomic conditions and other contextual factors, it may also reflect, in part, a reduction of misidentified suicide cases due to improving classification of manner of death.MethodWe compared the annual proportional change of suicide, undetermined death, and accidental death from South Korea with those of Japan and Hong Kong from 1992 to 2011; a greater proportional change of the manner-of-death categories during the period is indicative of a relatively less stable registration and hence a greater potential for misclassification bias on reported suicide trends. Subgroup analyses stratifying the deaths by methods were also conducted. To estimate the impact, the age-standardized rates of these three death categories in each site were calculated.ResultsWe found that, during the 20-year observation period, the proportional change of suicide, undetermined death, and accidental death in South Korea was significantly greater than Japan and Hong Kong. Similar observations were made in subgroup analyses. While death rates of the three manners in Japan and Hong Kong generally moved in a parallel fashion, the increase of suicide in South Korea occurred concomitantly with a significant reduction of its accidental death rate. 43% of the increase in suicides could be attributed to the decrease in accidental deaths, while 57% of the increase could be due to fundamental causes.ConclusionOur data suggest that, during the mid-1990s and after, the increasing burden of suicide in South Korea initially was masked, in part, by misclassification. Thus, the later apparently rapid increase of suicides reflected steadily improving classification of manner of death, as well as a more fundamental increase in the suicide rate.     

Levels of Bcl-2 and P53 Are Altered in Superior Frontal and Cerebellar Cortices of Autistic Subjects

1. Autistic disease (AD) is a severe neuropsychiatric disorder affecting 2-4 children per 10,000. We have recently shown reduction of Bcl-2 and increase in P53, two important markers of apoptosis, in parietal cortex of autistic subjects. 2. We hypothesized that brain levels of Bcl-2 and P53 would also be altered in superior frontal cortex and cerebellum of age-, sex, and postmortem-interval (PMI)-matched autistic subjects (N = 5 autistic, N = 4 controls). 3. Brain extracts were prepared from superior frontal cortex and cerebellum and subjected to Western blotting. 4. Results showed that levels of Bcl-2 decreased by 38% and 36% in autistic superior frontal and cerebellar cortices, respectively when compared to control tissues. By the same token, levels of P53 increased by 67.5% and 38% in the same brain areas in autistic subjects vs. controls respectively. Calculations of ratios of Bcl-2/P53 values also decreased by 75% and 43% in autistic frontal and cerebellar cortices vs. controls respectively. The autistic cerebellar values were significantly reduced (p < 0.08) vs. control only. There were no significant differences in levels of beta-actin between the two groups. Additionally, there were no correlations between Bcl-2, P53, and beta-actin concentrations vs. age or PMI in either group. 5. These results confirm and extend previous data that levels of Bcl-2 and P53 are altered in three important brain tissues, i.e. frontal, parietal, and cerebellar cortices of autistic subjects, alluding to deranged apoptotic mechanisms in autism.     

Alteration of Protease Levels in Different Brain Areas of Suicide Victims

Numerous recent studies found that proteases play a major role in brain function. In addition to their role in protein turnover, they have modulatory functions and an important role in apoptosis, pathological changes, and other mechanisms. To explore possible differences in brain protein metabolism of suicide victims, we examined the activity of two proteases, cathepsin D and calpain (I and II combined), in eleven discrete areas of postmortem brain tissue of 21 victims of suicide and of 31 age- and sex-matched control subjects without a history of psychiatric or neurological disease. The levels of functionally important amino acids in five of these areas were also measured. Cathepsin D activity was found to be lower in two of eleven regions of brains of suicide victims, the parahippocampal cortex and the medial hypothalamus, by 26% and 27%, respectively. Calpain activity was lower in two different areas tested, 29% in the medulla oblongata and 26% in the lateral prefrontal cortex, and was 18% higher in the midbrain. There were no significant differences in the other areas (globus pallidus, hippocampus, amygdala, caudate nucleus, ventral tegmental area, and nucleus accumbens). Protease distribution was regionally heterogeneous—the levels in the globus pallidus were low, and in the hippocampus high, with about a two-fold difference. The length of the postmortem period for obtaining tissue, the storage time of the frozen tissue, and the age of the subject had no apparent influence on the results obtained. Although there was a tendency toward higher levels of aspartate and glycine in brain areas from suicide victims, the difference was not significant. The variations among individual brains were greater in amino acid levels than in protease levels. The findings indicate the possible role of protein metabolism in depressive or suicidal behavior.     

Suicide among Manitoba's aboriginal people, 1988 to 1994

OBJECTIVE: To compare and contrast the characteristics of suicides among aboriginal and nonaboriginal people in Manitoba. DESIGN: Retrospective review of all suicides, based on a confidential analysis of records held by the Office of the Chief Medical Examiner. SETTING: Manitoba between 1988 and 1994. OUTCOME MEASURES: Standardized suicide rates, age- and sex-specific suicide rates, blood alcohol level at time of death, psychiatric help-seeking behaviour before suicide and residence on a reserve. RESULTS: Age-standardized suicide rates were 31.8 and 13.6 per 100,000 population per year among aboriginal and nonaboriginal people, respectively. The mean age of aboriginal people who committed suicide was 27.0 (standard deviation [SD] 10.8) years, compared with a mean age of 44.6 (SD 18.8) years for nonaboriginal people who committed suicide (p < 0.001). Blood alcohol levels at the time of death were a mean of 28 (SD 23) mmol/L among aboriginal people and 12 (SD 20) mmol/L among nonaboriginal people (p < 0.0001). Before their death, 21.9% of nonaboriginal suicide victims had sought psychiatric care whereas among aboriginal suicide victims 6.6% had sought care (p < 0.0001). Although the suicide rate was higher among aboriginal people living on reserve than among those living off reserve (52.9 v. 31.3 per 100,000 per year), both of these rates were substantially higher than the overall rates among nonaboriginal people. There were no significant differences in mean age, sex, blood alcohol level and previous psychiatric care among aboriginal people who committed suicide living on and off reserve. CONCLUSIONS: There was a high rate of suicide among Manitoba''s aboriginal people between 1988 and 1994; this rate was comparable to earlier estimates of national suicide rates among aboriginal people. The reserve environment does not, by itself, account for the high suicide rate among Manitoba''s aboriginal people. Further study of help-seeking behaviour and the association between alcohol abuse and suicide, particularly among aboriginal peoples, is indicated.     

Fatty acid composition of the postmortem prefrontal cortex of adolescent male and female suicide victims

Prior epidemiological, prospective intervention, and peripheral and central fatty acid composition studies suggest that omega-3 fatty acid deficiency may be associated with the pathoaetiology of depression and suicide. In the present study, we determined the fatty acid composition of the postmortem prefrontal cortex (PFC) of adolescent male and female suicide victims and age-matched controls. Fatty acid composition (wt% total fatty acids) and concentrations (μmol/g) were determined in the postmortem PFC (Brodmann area 10) of male and female adolescent (aged 13–20 years) suicide victims (n=20) and age-matched controls (n=20) by gas chromatography. None of the major polyunsaturated fatty acids including the principle brain omega-3 fatty acid, docosahexaenoic acid (DHA), monounsaturated fatty acids, or saturated fatty acids differed significantly between adolescent suicide victims and controls before or after segregation by gender. The arachidonic acid (AA, 20:4n-6): DHA ratio and adrenic acid (22:4n-6) composition were negatively correlated with age at death in controls but not in suicides, and males exhibited a greater AA:DHA ratio irrespective of cause-of-death. These results demonstrate that adolescent male and female suicide victims do not exhibit DHA deficits in the postmortem PFC relative to age-matched controls, and suggest that suicide victims do not exhibit the normal age-related decrease in adrenic acid composition and the AA:DHA ratio.     

Altered cAMP-dependent protein kinase subunit immunolabeling in post-mortem brain from patients with bipolar affective disorder

Previous findings of reduced [3H]cAMP binding and increased activities of cAMP-dependent protein kinase (PKA) in discrete post-mortem brain regions from patients with bipolar affective disorder (BD) suggest that PKA, the major downstream target of cAMP, is also affected in this illness. As prolonged elevation of intracellular cAMP levels can modify PKA regulatory (R) and catalytic (C) subunit levels, we sought to determine whether these PKA abnormalities are related to changes in the abundance of PKA subunits in BD brain. Using immunoblotting techniques along with PKA subunit isoform-specific polyclonal antisera, levels of PKA RIalpha, RIbeta, RIIalpha, RIIbeta and Calpha subunits were measured in cytosolic and particulate fractions of temporal, frontal and parietal cortices of post-mortem brain from BD patients and matched, non-neurological, non-psychiatric controls. Immunoreactive levels of cytosolic Calpha in temporal and frontal cortices, as well as that of cytosolic RIIbeta in temporal cortex, were significantly higher in the BD compared with the matched control brains. These changes were independent of age, post-mortem interval or pH and unrelated to ante-mortem lithium treatment or suicide. These findings strengthen further the notion that the cAMP/PKA signaling system is up-regulated in discrete cerebral cortical regions in BD.     

Muscarinic supersensitivity of anterior pituitary ACTH and B-endorphin release in major depressive illness

Subjects with major depressive illness had greater increases in plasma concentrations of ACTH and B-endorphin immunoreactivity in response to central muscarinic stimulation by physostigmine, than did normal control subjects, or psychiatric control subjects without major depressive illness. These findings provide further evidence for muscarinic receptor supersensitivity in depression and may implicate an abnormality of peptide physiology in the pathogenesis of depression.     

Regional Distribution and Relative Abundance of Serotonin2c Receptors in Human Brain: Effect of Suicide

Abnormalities in serotonin receptor subtypes have been observed in the postmortem brain of suicide victims. We examined the regional distribution of serotonin (5HT)(2C) receptor mRNA in several areas of the human brain and also compared its protein and mRNA expression in the prefrontal cortex (PFC), hippocampus, and choroid plexus between suicide victims and normal control subjects. 5HT(2C) receptors were found to be distributed in several areas of the human brain (in order of abundance): highly concentrated and richest in choroid plexus; hypothalamus; nucleus accumbens; with the lowest abundance in PFC and cerebellum. Comparison of 5HT(2C) receptors between suicide victims and control subjects showed higher protein levels in the PFC but not the hippocampus or choroid plexus of suicide victims. However, there were no significant differences in mRNA levels between suicide victims and control subjects in these brain areas. These results suggest that 5HT(2C) receptors are richly distributed throughout the brain with the highest level in the choroid plexus and that abnormalities in protein expression of 5HT(2C) receptors in the PFC may be associated with suicide.     

The association between catechol-O-methyl-transferase Val108/158Met polymorphism and suicide

One of the candidate genes for suicide is also a gene in the pathway for catecholamine degradation encoding an enzyme catechol-O-methyl-transferase (COMT). It harbors a common functional polymorphism, a G to A nucleotide transition resulting in amino acid substitution from valine (Val) to methionine (Met) at position 158 (COMT Val(108/158) Met; rs4680), that has been associated with psychiatric disorders characterized with an increased risk of suicidal behavior. We have performed the first study on Caucasian population examining the association between completed suicide and the COMT Val(108/158) Met polymorphism. The study population consisted of 356 suicide victims and 198 control subjects. Significant difference in COMT Val(108/158) Met variants' (genotypes, alleles and Val carriers) distribution was found only in male groups, between controls and suicide victims (P = 0.018, P = 0.031, P = 0.005), and between controls and violent suicide victims (P = 0.026, P = 0.042, P = 0.010). The r value from the standardized residuals showed that the Met/Met genotype (r = 2.03) in the control group contributed to these significant differences. In contrast to male subjects, no significant differences in the frequency of the COMT Val(108/158) Met variants were detected between female control and female suicide groups; however, the power of calculation (range 0.161-0.680) was below the desired 0.800. In addition, the logistic regression analysis confirmed these significant differences. In conclusion, our results showed the overpresentation of the Met/Met genotype in male control subjects compared with male suicide victims, suggesting that this genotype of the COMT Val(108/158) Met might be a protective factor against suicide.     

Global Brain Gene Expression Analysis Links Glutamatergic and GABAergic Alterations to Suicide and Major Depression

Background

Most studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations.

Methodology/Principal Findings

We performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data.

Conclusions/Significance

The observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions.     

Distribution, quantitation, and origin of immunoreactive neuropeptide Y in the human gastrointestinal tract

A radioimmunoassay for measurement of immunoreactive neuropeptide Y has been developed using antiserum from a rabbit (221) immunized with porcine neuropeptide Y. Antibody 221 has been characterized for both sensitivity and specificity. To determine the distribution of neuropeptide Y in the human gastrointestinal tract, fresh tissue specimens were separated by microdissection into the muscularis externa and the mucosa-submucosa. To examine the origin of neuropeptide Y in human colon, specimens of aganglionic and ganglionic colon were obtained from patients with Hirschsprung's disease. Immunoreactive neuropeptide Y in human gut was present in highest concentrations in the muscularis externa of the stomach and in lowest concentrations in the muscularis externa of the ileum and descending colon. Neuropeptide Y in the stomach was present in higher concentrations in the muscularis externa than in the mucosa-submucosa, but in the descending colon there were lower concentrations of neuropeptide Y in the muscularis externa than in the mucosa-submucosa. In Hirschsprung's disease, concentrations of neuropeptide Y were increased in aganglionic colon in both the muscularis externa and the mucosa-submucosa, compared to corresponding layers from proximal ganglionic colon. Extracts of the gastric muscularis externa and the colonic mucosa-submucosa were separated by C18 reverse-phase high-performance liquid chromatography. One major immunoreactive species was identified by radioimmunoassay which eluted in a position similar to synthetic human neuropeptide Y. These results demonstrated both regional and layer differences in concentrations of neuropeptide Y in human gut. Increased concentrations of neuropeptide Y in aganglionic colon from Hirschsprung's disease most likely result from enlargement of neuropeptide Y-containing extrinsic nerve fibers in both the mucosa-submucosa and the muscularis externa.