Félicien Karege

Decreased serum brain-derived neurotrophic factor levels in major depressed patients.

Recent findings with animal models have suggested a possible role for brain-derived neurotrophic factor (BDNF) in depression. We have therefore hypothesized that depression could be characterized by low levels of serum BDNF. Major depressed patients (15F + 15M) diagnosed according to DSM-IV criteria and healthy controls (15F + 15M) participated in the study. Serum BDNF was assayed with the ELISA method and the severity of depression was evaluated with Montgomery-Asberg-Depression Rating Scale (MADRS). BDNF levels were significantly lower in patients than in controls: 22.6 +/- 3 and 26.5 +/- 7 ng/ml (t-test = 2.7; d.f. = 58; P < 0.01). They were negatively correlated to the MADRS scores (r = -0.55; P < 0.02). Female patients were more depressed and released less BDNF than men. Analysis of covariance (MADRS and gender as independent variable vs. BDNF as dependent variable) indicated that depression severity mainly accounted for the negative correlation. These results suggest that major depression is characterized by low serum BDNF levels and support the hypothesis of neurotrophic factor involvement in affective disorders.

Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets

The brain-derived neurotrophic factor (BDNF) has been involved in pre- and postnatal brain development. Moreover, abundant levels of this neurotrophin have been found in animal and human brain and serum. This study was aimed to assess the postnatal change profile of both serum and brain BDNF levels. By using immunoassay and reverse transcription-polymerase chain reaction methods, BDNF protein and mRNA levels were determined in serum and platelets, respectively, and in two brain structures (hippocampus and frontal cortex) of postnatal rats (one and three weeks old), young adults (two months old) and in aged animals (two years old). The results showed that brain and serum BDNF levels underwent similar changes during maturation and aging processes (analysis of variance (ANOVA): P<0.001, P<0.001, for hippocampus and serum, respectively). During the same investigation period, the measure of BDNF mRNA indicated gradual changes in the hippocampus but not in platelets (ANOVA: P<0.001 and not significant, for hippocampus and platelets, respectively). Interestingly, there was a positive correlation between serum and cortical BDNF levels (r=0.81, P<0.01), especially in young animals. This study of ontogenic characteristics of BDNF in blood and central nervous system can help to shed more light on the role of platelet BDNF.

Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity.

BACKGROUND Recent reports have suggested a role for brain-derived neurotrophic factor (BDNF) in psychiatric disorders. Decreased serum BDNF levels have been reported in major depression, but the cause of this decrease has not yet been investigated. The goal of this study was to assess blood BDNF and a platelet activation index, PF4. METHODS Forty-three drug-free patients (27 female, 16 male) diagnosed with major depression and 35 healthy control subjects (18 female, 17 male) were assessed for plasma, serum, and blood BDNF content. Brain-derived neurotrophic factor and PF4 were assayed with enzyme-linked immunosorbent assay methods, and severity of depression was evaluated with the Montgomery-Asberg Depression Rating Scale. RESULTS Serum and plasma BDNF levels were decreased in depressed patients compared with control subjects. In whole blood, BDNF levels were unaltered in the depressed subjects compared with control subjects. The serum/blood BDNF ratio was lower in patients with major depression. Increased plasma but not serum PF4 levels were observed in depressed subjects compared with control subjects. CONCLUSIONS Our results suggest that an alteration of serum or plasma BDNF is not due to the change in blood BDNF but rather is probably related to mechanisms of BDNF release. Secretion of BDNF seems to be independent of platelet reactivity; other mechanisms are therefore probably involved and need to be elucidated.

Partial normalization of serum brain-derived neurotrophic factor in remitted patients after a major depressive episode.

We had previously reported decreased serum brain-derived neurotrophic factor (BDNF) levels in depressed patients. In the present study, we tested the hypothesis that antidepressant treatment would normalize serum BDNF levels, at least in a subgroup of patients. Major depressed patients (15 females and 11 males) diagnosed according to DSM-IV criteria and healthy controls (13 females and 13 males) participated in this study. Serum BDNF was assayed with the ELISA method for depressed and remitted patients and the severity of depression was evaluated with the Montgomery-Asberg Depression Rating Scale. An analysis of variance showed that treatment had an effect [F(1, 24) = 4.46, p = 0.045] on the normalization of serum BDNF levels. We also found a correlation between the severity of depression (r = 0.51, p = 0.008), the pretreatment BDNF levels (r = 0.62, p = 0.001) and the difference in serum BDNF levels after antidepressant treatment. These results suggest that antidepressant treatment has a positive effect on serum BDNF levels and support the hypothesis of neurotrophic factor involvement in affective disorders.

Increased DNA methylation status of the serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder

BACKGROUND Epigenetic changes may play a role in the etiology of psychotic diseases. It has been demonstrated that the serotonin receptor, 5HTR1A, is implicated in schizophrenia (SCZ) and bipolar disorder (BPD). The aim of this study was to investigate the methylation status of a promoter region of the 5HTR1A gene in BPD and SCZ patients. METHODS Our study included 58 BPD and 40 SCZ (DSM-IV criteria) as well as 67 control subjects. DNA was extracted from blood leukocytes and high-resolution melt (HRM) method was used for analysis. RESULTS Non-parametric analysis of variance (Kruskal-Wallis) within groups was significant: H=67.6; p<0.0001. The Mann-Whitney U-test showed increased methylation level in both BPD (Z=-7.4; p<0.0001) and SCZ (Z=4.2; p<0.0001) compared to controls. No effect either of age or gender by own, was observed. ANCOVA revealed a modest effect of age/gender covariance (F=3.99; p<0.048). LIMITATION We used a peripheral tissue. The relationship between methylation of blood and brain DNA is not well known. Data need to be replicated in a brain tissue. CONCLUSION We observed increased DNA methylation in the promoter region of the 5HTR1A gene of SCZ and BPD. This could explain the reported decrease of the receptor expression. The current study supports the growing interest of DNA methylation in psychopathology.

The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis

Abstract Objectives. Transmission of parental post-traumatic stress disorder (PTSD) to offspring might be explained by transmission of epigenetic processes such as methylation status of the glucocorticoid receptor (GR) gene (NR3C1). Methods. We investigated PTSD and depression severity, plasma cortisol, GR and mineralocorticoid receptor (MR) levels, and methylation status of NR3C1 and NR3C2 promoter regions in 25 women exposed to the Tutsi genocide during pregnancy and their children, and 25 women from the same ethnicity, pregnant during the same period but not exposed to the genocide, and their children. Results. Transmission of PTSD to the offspring was associated with transmission of biological alterations of the HPA axis. Mothers exposed to the genocide as well as their children had lower cortisol and GR levels and higher MR levels than non-exposed mothers and their children. Moreover, exposed mothers and their children had higher methylation of the NR3C1 exon 1F than non-exposed groups. Finally, exposed mothers showed higher methylation of CpGs located within the NR3C2 coding sequence than non-exposed mothers. Conclusions. PTSD was associated with NR3C1 epigenetic modifications that were similarly found in the mothers and their offspring, modifications that may underlie the possible transmission of biological alterations of the HPA axis.

Early effects of mood stabilizers on the Akt/GSK-3β signaling pathway and on cell survival and proliferation

RationaleLithium, some of the anticonvulsants, and several second-generation antipsychotic drugs are common medications widely prescribed to treat bipolar disorder. Molecular targets and cellular events that mediate their effects have been described for these drugs but are only partially unraveled. Few comparative studies have been performed.ObjectivesWe evaluated seven mood stabilizers (MS) in the same in vitro system and found several differences and similarities in their cellular mechanisms (proliferation and cell survival). As some MS were previously shown to activate the Akt/GSK-3β axis, this pathway was explored for other drugs.Materials and methodsThe SH-SY5Y cells were cultured in RPMI-1640 medium. Effects of MS drugs on serum-induced cell proliferation and on slowing of cell death were analyzed. Phosphorylation and expression of Akt-1 and GSK-3β mRNA and protein were assessed for the seven drugs as well.ResultsLithium, Valproate, Olanzapine, and Clozapine enhance proliferation and protect cells against serum withdrawal-induced injury. These drugs also activate Akt-1 and GSK-3β phosphorylation. Interestingly, gene expression of Akt-1 mRNA and protein, but not GSK-3β, was increased. The other drugs Lamotrigine, Haloperidol, and Carbamazepine did not affect cellular events nor activate Akt/GSK-3β axis.ConclusionValproate and atypical antipsychotics (Olanzapine and Clozapine) regulate SH-SY5Y cell proliferation and survival, activate the Akt/GSK-3β axis, and stimulate gene expression of Akt-1 mRNA and protein, as does Lithium. The other medications have no effect. The study shows the importance of the Akt/GSK-3 axis in MS actions but also pinpoints a different dependence of these drugs on this signaling axis.

Association between brain-derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter gene

BACKGROUND Recent data suggest that brain-derived neurotrophic factor (BDNF) and the serotonergic system are involved and interact in major depressive disorder and suicidal behavior (SB). Several family and population-based studies have reported associations between the BDNF gene and serotonin-related genes, specifically the serotonin transporter (5HTT) gene, with bipolar disorder (BD) and SB. However, despite the fact that gene-by-gene interaction between BDNF and 5HTT has been demonstrated in monoamine deficiencies in animals, this kind of interaction has never been tested in humans. Our hypothesis is that some BDNF and 5HTT polymorphisms might confer increased risk for BD and SB and that both genes may interact with each other. METHODS To test this hypothesis, we genotyped the most common BDNF polymorphisms, G196A (Val66Met), A-633T and BDNF-LCPR, as well as 5HTT (5HTT-LPR), in 447 BD patients and 370 controls. RESULTS We replicated the association previously reported between BDNF G196A (Val66Met) polymorphism and BD. We also observed a correlation between the number of G196 alleles and short alleles of 5HTT-LPR and the severity of SB in BD. However, we found no significant interaction between these two markers. CONCLUSIONS These results suggest that BDNF G196A as well as 5HTT-LPR polymorphisms confer risk for SB in BD, but we did not observe any evidence for an interaction between them.

A non-radioactive assay for the cAMP-dependent protein kinase activity in rat brain homogenates and age-related changes in hippocampus and cortex

Cyclic AMP-dependent protein kinase (PKA) activity was involved in a number of brain functions such as cognitive process or aging. The measurement of PKA activity is traditionally based on the use of [(32)P]ATP in phosphorylation of specific protein. Recently non-isotopic PKA assays have been developed, but none has been tested on brain homogenates. This work aimed to adapt a fluorimetric method of PKA activity into a novel assay never applied before in brain homogenate, and to characterize the enzyme activity and ratio in hippocampus and cortex from rats of different ages. Optimal conditions of homogenization and enzyme protection were determined. The method was sensitive and reproducible (intra-assay and interassay variation was 5.0% and 9.0%, respectively). In hippocampal cytosol, PKA activity was 27+/-8 and 80+/-9 nmol/min per mg protein in basal and cAMP-stimulated activity, respectively, and accounted for 80% of total cell PKA activity. The non-PKA activity, assessed by the use of the PKA specific inhibitor (PKI) accounted for 49.0% and 65.0% of endogenous levels in cytosol and membrane, respectively. cAMP-augmenting drugs effects were measured and increase of 53%, 273% and 118% over basal by 10 microM isoproterenol, 100 microM forskolin, 1 microM Sp-AMP, respectively, was observed. With respect to the changes in animal age, PKA activity increased from newborn to the mature rats but decreased in older rats. The PKA ratio was higher in cytosol than in particulate fraction, and was decreased in hippocampal sample from old rats (P<0.05). This last result was interpreted as related to the loss of cognitive capacities in old animals.

The cAMP-dependent protein kinase A and brain-derived neurotrophic factor expression in lymphoblast cells of bipolar affective disorder

BACKGROUND Abnormalities in cAMP signaling and altered expression of downstream targets such as brain-derived neurotrophic factor (BDNF) have been postulated in patients with bipolar disorder (BD). METHODS The PKA activity and levels of (3)H-cAMP binding to PKA R regulatory subunits were measured in lymphoblasts from 10 BD and 10 control subjects. In addition, the possibility that BDNF expression could be altered in these cells has been explored. RESULTS Results indicate that PKA activity significantly increased (t-test; P<0.01), whereas the (3)H-cAMP binding to PKA R subunits decreased in cells from BD (t-test; P<0.02). The presence of 10 microM Sp-cAMP in culture 24 h before cell harvesting induced an increase in enzyme activity and a decrease in (3)H-cAMP binding sites (t-test; P<0.01), with a significant difference between BD and controls (t-test; P<0.01). This presence of Sp-cAMP also results in increased BDNF expression (t-test, P<0.01), but neither in resting cells, nor in stimulated cells, was any difference observed in BDNF expression between BD and controls (t-test, NS). LIMITATIONS This study was conducted on a peripheral model cell, whose importance of BDNF is unknown. CONCLUSIONS These data suggest that the upregulation of cAMP signaling observed in BD patients results in the normalization of the BDNF expression. Studies on signal transduction, gene expression and pathologies have implications for development of novel treatments.