Biomedical subjects

Florian Holsboer

Publications and source records attributed to Florian Holsboer.

At least 19 recordsLinked to original sources

PubMed2007

The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction.

Glucocorticoids (GCs) immunosuppression acts via regulation of several transcription factors (TF), including activating protein (AP)-1, NF-kappaB, and NFAT. GCs inhibit Th1 cytokines and promote a shift toward Th2 differentiation. Th1 phenotype depends on TF T-bet. In this study, we examined GC regulation of T-bet. We found that GCs inhibit T-bet transcriptional activity. We show that glucocorticoid receptor (GR) physically interacts with T-bet both in transfected cell lines and in primary splenocyte cultures with endogenous GR and T-bet. This interaction also blocks GR-dependent transcription. We show both in vitro and in vivo at endogenous binding sites that the mechanism underlying T-bet inhibition further involves reduction of T-bet binding to DNA. Using specific mutations of GR, we demonstrate that the first zinc finger region of GR is required for T-bet inhibition. GCs additionally inhibit T-bet both at mRNA and protein expression levels, revealing another layer of GR action on T-bet. Finally, we examined the functional consequences of GR/T-bet interaction on IFN-gamma, showing that GCs inhibit transcriptional activity of T-bet on its promoter. In view of the crucial role of T-bet in T cell differentiation and inflammation, we propose that GR inhibitory interaction with T-bet may be an important mechanism underlying the immunosuppressive properties of GCs.

Animals↗

PubMed2007

Association of polymorphisms in P2RX7 and CaMKKb with anxiety disorders.

BACKGROUND: There is considerable evidence that genetic factors play an important role in the pathophysiology of affective disorders including bipolar disorder, major depressive disorder and anxiety disorders. Long-term follow up studies as well as drug treatment studies suggest that these clinical conditions share a number of pathophysiological commonalities including genetic variables. One possible candidate region is located on chromosome 12q24.31, originated from previous linkage and association studies with bipolar disorder and unipolar depression. This region contains two candidate genes for purinergic ligand-gated ion channels, P2RX7 and P2RX4, and one gene coding for calmodulin-dependent protein kinase kinase b (CaMKKb). METHODS: In the present study, we investigated the genetic associations between 15 SNPs in the candidate genes P2RX7, P2RX4 and CaMKKb on chromosome 12q24.31 in 179 patients with anxiety disorders and syndromal panic attacks versus 462 healthy controls. RESULTS: One nominal case-control association could be detected for a SNP in the 5'UTR region of P2RX4, which did not remain significant after correction for multiple testing. We found, however, a prominent association between severity of panic- and agoraphobia symptoms and an exonic SNP (rs3817190) in the CaMKKb gene and a trend for association with an exonic SNP in P2RX7 (rs1718119) with severity scores in the panic- and agoraphobia scale. CONCLUSION: The locus 12q24.31 seems to be an important genetic region for anxiety, bipolar and unipolar disorders, suggesting a genetic overlap in the group of affective disorders. The specific contribution of the herein reported gene polymorphisms to the clinical condition is still unclear and warrants further analysis.

Adult↗

PubMed2007

Acute and chronic neuroendocrine effects of interferon-beta 1a in multiple sclerosis.

OBJECTIVE: Treatment of multiple sclerosis with interferon-beta (IFN-beta) results in variable responses interindividually. Cytokine-hormone interactions may modulate the therapeutic effects of IFN-beta. Since hyperactivity of the hypothalamo-pituitary-adrenal (HPA) axis and other neuroendorine disturbances occur in multiple sclerosis, we determined the detailed neuroendocrine response of patients with multiple sclerosis to IFN-beta. DESIGN: Longitudinal open-label study. PATIENTS: Eight patients with relapsing-remitting multiple sclerosis (four women, age 31.9 +/- 1.5 years, EDSS 1.5-2.5). MEASUREMENTS: Plasma ACTH, cortisol, prolactin, GH, TSH, LH and FSH were determined in 30-min intervals during 8 h on four occasions: after intramuscular injection of saline; after the first dose of IFN-beta 1a; after the second IFN-beta dose with oral indomethacin pretreatment; and after 3 months of IFN-beta therapy. Dexamethasone-corticotropin-releasing hormone test was performed before and at 3 months on IFN-beta. RESULTS: Compared to saline, IFN injection resulted in marked rise in plasma ACTH (mean, 370% of baseline), cortisol (214%), prolactin (253%) and GH (756%), between 2 and 6 h after injection. With indomethacin, hormone secretion occurred with reduced peak values. Endocrine response adapted partially after 3 months of treatment. HPA axis activity decreased in most patients, but increased in one patient with frequent relapses. CONCLUSIONS: Marked neuroendocrine effects occur in response to IFN-beta in multiple sclerosis. Upon prolonged treatment, these effects partially adapt, and HPA axis hyperactivity is reduced. Prospective studies to determine the relation to individual treatment response can be based on these findings.

Adrenocorticotropic Hormone↗

PubMed2006

Persistent cognitive impairment in depression: the role of psychopathology and altered hypothalamic-pituitary-adrenocortical (HPA) system regulation.

BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system and cognitive impairment are consistent findings in depression. This study examines the associations between HPA system regulation, cognitive functioning, and psychopathology in depressed inpatients on admission and at discharge. METHODS: The HPA system dysregulation was evaluated with the dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. Cognitive assessment included speed of information processing, divided and selective attention, as well as short-term and working memory. Psychopathology was evaluated with the Hamilton Rating Scale for Depression (HAMD). Data from 75 depressed inpatients are reported, 51 (68%) of them achieved remission. RESULTS: Despite a significant reduction of depressive symptoms between admission and discharge, a high rate of patients remained cognitively impaired. Selective attention improved significantly in remitters and nonremitters, while speed of information processing increased only in remitters. The cortisol response to the DEX/CRH test decreased significantly only in remitters, which was uncorrelated with cognitive performance. In nonremitters, severity of depression was significantly correlated with information processing time while improvement in short-term memory was negatively associated with the cortisol response at discharge. CONCLUSIONS: Our data support the assumption that psychopathological symptoms and the HPA system dysregulation can be dissociated in their impact on cognitive functioning in depressed patients.

Adult↗

PubMed2006

Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression - a potential biomarker?

BACKGROUND: Exaggerated corticotropin (ACTH) and cortisol response to the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test, indicating impaired regulation of the hypothalamus-pituitary-adrenocortical (HPA) system, is frequently observed in depression. In the present study, we examined whether change in HPA system function during the first weeks of hospitalization predicts response to antidepressant treatment in major depression and thus constitutes a potential biomarker. METHODS: We conducted the DEX/CRH test in 50 inpatients suffering from severe major depression, once after study inclusion and a second time 2 to 3 weeks later while under continuous antidepressant treatment. RESULTS: We found increased ACTH and cortisol responses to the first DEX/CRH test compared with healthy control subjects. In the second DEX/CRH test 2 to 3 weeks later, 36 of the 50 patients showed an attenuated cortisol response, while 14 patients did not display improvement or exhibited even aggravation of the altered HPA system function. Improved HPA system regulation in the second DEX/CRH test was associated with beneficial treatment response after 5 weeks and a higher remission rate at the end of hospitalization. CONCLUSIONS: The results suggest that change in HPA system regulation assessed with repeated DEX/CRH tests is a potential biomarker that may predict clinical outcome at follow-up. There is consensus that the drug development process could be improved, once reliable biomarkers become available that help to allow a judgement regarding the efficacy of a novel drug candidate. The combined DEX/CRH test seems to be a promising candidate for such a biomarker.

Adrenocorticotropic Hormone↗

PubMed2006

Immune-endocrine host response to endotoxin in major depression.

OBJECTIVE: An impaired hypothalamic-pituitary-adrenocortical (HPA) function is a well-established finding in major depression (MD), but it is still unclear how this dysfunction affects immune responses in this disorder. METHOD: To further examine the relationship between immune and endocrine responses in MD, 0.4ng/kg body weight endotoxin [LPS] or 100mug hCRH were sequentially applied to 12 patients with MD and to 12 age- and gender-matched healthy controls after pre-treatment with 1.5mg dexamethasone (DEX). Immune (TNF-alpha, IL-6, rectal temperature) and endocrine (ACTH, cortisol) parameters were examined as area under the curve (AUC) levels. RESULTS: After pre-treatment with DEX, LPS evoked an immune response in all participants of the study with most immune parameters significantly related to the endotoxin challenge. However, only a marked immune response resulted in an additional endocrine reaction. Subsequently, the quantitative extent of the endocrine reaction was related to the extent of the immune response after DEX/LPS challenge. Pre-LPS AUC levels of cortisol, ACTH and post-LPS levels of IL-6 as well as the post-CRH AUC levels of cortisol and ACTH were related to the depressive symptomatology as measured by the Beck depression inventory (BDI). In depressive patients who showed increased cortisol plasma levels before LPS, the later increase in IL-6 was reduced. CONCLUSIONS: The challenge with DEX/LPS did not reveal major impairments of evoked immune functions in MD. Only the endocrine parameters and the IL-6 response were related to the depressive symptomatology, suggesting a limited interaction between immune and endocrine dysfunctions in MD.

Adrenocorticotropic Hormone↗

PubMed2006

Successful antidepressant therapy restores the disturbed interplay between TNF-alpha system and HPA axis.

BACKGROUND: In depressed patients, alterations in the hypothalamo-pituitary-adrenocortical (HPA) system are the most consistent neurobiological finding. HPA axis activity and cytokines are intrinsically intertwined: inflammatory cytokines stimulate adrenocorticotropic hormone (ACTH) and cortisol secretion, while, in turn, glucocorticoids suppress the synthesis of proinflammatory cytokines. METHODS: We examined alterations in plasma levels of tumor necrosis factor-alpha (TNF-alpha), levels of its soluble receptors p55 (sTNF-R p55) and p75 (sTNF-R p75) as well as changes in the HPA system function using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test on admission and at discharge in 70 depressed inpatients without inflammation. RESULTS: On admission, TNF-alpha levels were inversely associated with the ACTH response to the combined dex/CRH test. Changes in TNF-alpha, sTNF-R p55, and sTNF-R p75 plasma levels from admission to discharge were positively correlated with the dex/CRH test outcome at discharge. Subgroup analysis revealed that this association was restricted to those patients achieving remission. In this subgroup, TNF-alpha levels at discharge were also positively correlated with dex/CRH test response at discharge. CONCLUSIONS: Our results suggest that elevated HPA axis activity in acute depression suppresses TNF-alpha system activity, while after remission, when HPA axis activity has normalized, the TNF-alpha system seems to gain influence on the HPA system.

Adult↗

PubMed2006

Conditional CRF receptor 1 knockout mice show altered neuronal activation pattern to mild anxiogenic challenge.

RATIONALE: Regional-specific corticotropin-releasing factor receptor 1 (CRF-R1) knockout mice have been generated recently as a tool to dissociate CNS functions modulated by this receptor. In these mice, CRF-R1 function is postnatally inactivated in the anterior forebrain including limbic brain structures but not in the pituitary leading to normal activity of the hypothalamic-pituitary-adrenocortical (HPA) axis under basal conditions and reduced anxiety-related behavior in the light-dark box and the elevated plus maze (EPM) as compared to wild-type (WT) mice (Müller et al., Nat Neurosci 6:1100-1107, 2003). OBJECTIVE: To identify neurobiological correlates underlying this reduced anxiety-like behavior, the expression of c-Fos, an established marker for neuronal activation, which was examined in response to a mild anxiogenic challenge. MATERIALS AND METHODS: Mice were placed for 10 min on the open arm (OA) of the EPM, and regional c-Fos expression was investigated by immunohistochemistry. RESULTS: OA exposure enhanced c-Fos expression in both conditional CRF-R1 knockout and WT mice in a number of brain areas (39 of 55 quantified), including cortical, limbic, thalamic, hypothalamic, and hindbrain regions. The c-Fos response in conditional CRF-R1 knockout animals was reduced in a restricted subset of activated neurons (4 out of 39 regions) located in the medial amygdala, ventral lateral septum, prelimbic cortex, and dorsomedial hypothalamus. CONCLUSIONS: These results underline the importance of limbic CRF-R1 in modulating anxiety-related behavior and suggest that reduced neuronal activation in the identified limbic and hypothalamic key structures of the anxiety circuitry may mediate or contribute to the anxiolytic-like phenotype observed in mice with region-specific deletion of forebrain CRF-R1.

Amygdala↗

PubMed2006

CRF signaling: molecular specificity for drug targeting in the CNS.

Corticotrophin-releasing factor (CRF) is the key mediator of the central nervous system response needed to adapt to stress. If adaptation fails, hypersecretion of CRF continues and produces, via CRF type 1 receptors, symptoms pertaining to cognition, appetite, sleep and anxiety, implicating CRF as a causal factor in affective disorders. Clinical studies with CRF receptor 1 antagonists support a novel pharmacological strategy for treating stress-related disorders. Here we summarize recent information obtained on CRF receptor 1 signaling and propose the concept of a more focused pharmacological intervention based on the signaling pathways involved. Recent findings suggest that CRF activates, via the same CRF receptor 1, different signaling pathways in specific areas of the brain. This intracellular and neuroanatomical signaling specificity will facilitate the search for less pleiotropic antagonists and new chemical compounds that modulate signal transduction in a site-specific manner.

Animals↗

PubMed2006

Association of a Met88Val diazepam binding inhibitor (DBI) gene polymorphism and anxiety disorders with panic attacks.

Several lines of evidence suggest that anxiety disorders have a strong genetic component, but so far only few susceptibility genes have been identified. There is preclinical and clinical evidence for a dysregulation of the central gamma-aminobutyric acid (GABA)-ergic tone in the pathophysiology of anxiety disorders. Diazepam binding inhibitor (DBI) has been suggested to play a pivotal role in anxiety disorders through direct and indirect, i.e. via synthesis of neuroactive steroids, modulation of GABA(A) receptor function. These findings suggest that the DBI gene can be postulated as a candidate for a genetic association study in this disorder. Thus, single nucleotide polymorphisms (SNPs) of the DBI gene were investigated for putative disease associations in a German sample of anxiety disorder patients suffering from panic attacks and matched controls. We were able to detect a significant association between a non-synonymous coding variant of DBI with anxiety disorders with panic attacks. The rare allele of this polymorphism was more frequent in controls than in patients (OR=0.43; 95% CI: 0.19-0.95). In conclusion, these results suggest a central role of DBI genetic variants in the susceptibility for the development of anxiety disorders that are characterized by the occurrence of panic attacks.

Adult↗

PubMed2006

Regulation of the hypothalamic-pituitary-adrenocortical system in patients with panic disorder.

Anxiety and depressive disorders are among the most common psychiatric disorders with a high number of hospital admissions and a lifetime prevalence of up to 25%. So far, the pathophysiological mechanisms for anxiety disorders remain to be found. Preclinical studies suggest that changes in hypothalamic-pituitary-adrenocortical (HPA) system function are causally related to the expression of anxiety-related behavior. The findings on HPA system function in patients with anxiety disorders are, however, heterogeneous. Both hypo- and hyperresponsiveness of HPA response in various anxiety disorders under different experimental conditions were found. In order to characterize putative case/control differences in HPA system function, we performed a Dex-CRH test, a widely used test to pick up changes in HPA system regulation with high sensitivity, in 30 patients with panic disorder, 35 patients with major depressive episode and in 30 controls individually matched for ethnicity, age and gender. The results indicate a similar dysregulation of the HPA system response in the Dex-CRH test in both patient groups. This finding further underlines the hypothesis that both, depression and panic disorder, share impaired HPA system regulation, supporting the notion that the impairment is involved in the pathophysiology of these clinical conditions. However, differences in the suppression effects and psychopathological correlation patterns between depressed and panic patients suggest different biological mechanisms of HPA system dysregulation in both disorders.

Adrenocorticotropic Hormone↗

PubMed2006

P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder.

The P2RX7 gene is located within a region on chromosome 12q24.31 that has been identified as a susceptibility locus for affective disorders by linkage and association studies. P2RX7 is a purinergic ATP-binding calcium channel expressed in neurons as well as in microglial cells in various brain regions. We investigated 29 single nucleotide polymorphisms (SNPs) within the P2RX7 gene and adjacent genes in a sample of 1000 German Caucasian patients suffering from recurrent major depressive disorder (MDD). These were contrasted with diagnosed healthy Caucasian controls from the same population (n=1029). A non-synonymous coding SNP in the P2RX7 gene (rs2230912), previously found to be associated with bipolar disorder, was significantly associated (P=0.0019) with MDD. This polymorphism results in an amino acid exchange in the C-terminal cytosolic domain of the P2RX7 channel protein, suggesting that the observed P2RX7 polymorphism might play a causal role in the development of depression.

Adult↗

PubMed2006

Protein biomarkers in a mouse model of extremes in trait anxiety.

Brain proteome analysis of mice selectively bred for either high or low anxiety-related behavior revealed quantitative and qualitative protein expression differences. The enzyme glyoxalase-I was consistently expressed to a higher extent in low anxiety as compared with high anxiety mice in several brain areas. The same phenotype-dependent difference was also found in red blood cells with normal and cross-mated animals showing intermediate expression profiles of glyoxalase-I. Another protein that showed a different mobility during two-dimensional gel electrophoresis was identified as enolase phosphatase. The presence of both protein markers in red or white blood cells, respectively, creates the opportunity to screen for their expression in clinical blood specimens from patients suffering from anxiety.

Amygdala↗

PubMed2006

Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder.

Previous results from our genetic analyses using pedigrees from a French Canadian population suggested that the interval delimited by markers on chromosome 12, D12S86 and D12S378, was the most probable genomic region to contain a susceptibility gene for affective disorders. Association studies with microsatellite markers using a case/control sample from the same population (n = 427) revealed significant allelic associations between the bipolar phenotype and marker NBG6. Since this marker is located in intron 9 of the P2RX7 gene, we analyzed the surrounding genomic region for the presence of polymorphisms in regulatory, coding and intron/exon junction sequences. Twenty four (24) SNPs were genotyped in a case/control sample and 12 SNPs in all pedigrees used for linkage analysis. Allelic, genotypic or family-based association studies suggest the presence of two susceptibility loci, the P2RX7 and CaMKK2 genes. The strongest association was observed in bipolar families at the non-synonymous SNP P2RX7-E13A (rs2230912, P-value = 0.000708), which results from an over-transmission of the mutant G-allele to affected offspring. This Gln460Arg polymorphism occurs at an amino acid that is conserved between humans and rodents and is located in the C-terminal domain of the P2X7 receptor, known to be essential for normal P2RX7 function.

Alleles↗

PubMed2006

Retinoic acid as a novel medical therapy for Cushing's disease in dogs.

Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease.

Adenoma↗

PubMed2006

Monthly intravenous methylprednisolone in relapsing-remitting multiple sclerosis - reduction of enhancing lesions, T2 lesion volume and plasma prolactin concentrations.

BACKGROUND: Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) relapses, accompanied by rapid, though transient reduction of gadolinium enhancing (Gd+) lesions on brain MRI. Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses. METHODS: In an open, single-cross-over study, nine patients with relapsing-remitting MS (RR-MS) underwent cranial Gd-MRI once monthly for twelve months. From month six on, they received a single i.v.-infusion of 500 mg methylprednisolone (and oral tapering for three days) after the MRI. Primary outcome measure was the mean number of Gd+ lesions during treatment vs. baseline periods; T2 lesion volume and monthly plasma concentrations of cortisol, ACTH and prolactin were secondary outcome measures. Safety was assessed clinically, by routine laboratory and bone mineral density measurements. Soluble immune parameters (sTNF-RI, sTNF-RII, IL1-ra and sVCAM-1) and neuroendocrine tests (ACTH test, combined dexamethasone/CRH test) were additionally analyzed. RESULTS: Comparing treatment to baseline periods, the number of Gd+ lesions/scan was reduced in eight of the nine patients, by a median of 43.8% (p = 0.013, Wilcoxon). In comparison, a pooled dataset of 83 untreated RR-MS patients from several studies, selected by the same clinical and MRI criteria, showed a non-significant decrease by a median of 14% (p = 0.32). T2 lesion volume decreased by 21% during treatment (p = 0.001). Monthly plasma prolactin showed a parallel decline (p = 0.027), with significant cross-correlation with the number of Gd+ lesions. Other hormones and immune system variables were unchanged, as were ACTH test and dexamethasone-CRH test. Treatment was well tolerated; routine laboratory and bone mineral density were unchanged. CONCLUSION: Monthly IV-MP reduces inflammatory activity and T2 lesion volume in RR-MS.

Adult↗

PubMed2006

Polymorphisms of the glucocorticoid receptor gene and major depression.

BACKGROUND: The most consistent biological finding in patients with depression is a hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis, which might be caused by impaired glucocorticoid signaling. Glucocorticoids act through the glucocorticoid receptor (GR) for which several polymorphisms have been described. The N363S and BclI polymorphisms have been associated with hypersensitivity to glucocorticoids, whereas the ER22/23EK polymorphism is related to glucocorticoid resistance. METHODS: We studied whether the susceptibility to develop a depression is related to these polymorphisms by comparing depressive inpatients (n = 490) and healthy control subjects (n = 496). Among depressed patients, we also investigated the relation between GR variants and dysregulation of the HPA-axis, as measured by the combined dexamethasone suppression/corticotropin-releasing hormone (CRH)-stimulation test, clinical response to antidepressive treatment, and cognitive functioning. RESULTS: Homozygous carriers of the BclI polymorphism and ER22/23EK-carriers had an increased risk of developing a major depressive episode. We found no genetic associations with functional HPA-axis measures in depressed patients. The ER22/23EK-carriers, however, showed a significantly faster clinical response to antidepressant therapy as well as a trend toward better cognitive functioning during depression. CONCLUSIONS: The BclI and ER22/23EK polymorphisms were associated with susceptibility to develop major depression. In addition, the ER22/23EK polymorphism is associated with a faster clinical response to antidepressant treatment. These findings support the notion that variants of the GR gene might play a role in the pathophysiology of a major depression and can contribute to the variability of antidepressant response.

Adult↗

PubMed2006

Mice with mutations in the HPA-system as models for symptoms of depression.

Genetically engineered mice hold promise to help us understand the effects of enhanced or reduced gene activity upon behavior and metabolism. Because many basic and clinical studies suggest that alterations of the hypothalamic pituitary adrenocortical (HPA) system are involved in the development and course of depression, mouse mutants with genetic modifications of genes regulating the HPA system were generated. This review summarizes these effects and concludes that advanced technologies allowing for regional overexpression or inactivation of genes or introduction of polymorphisms into the mouse genome are well suited to explain individual symptoms or symptom patterns prevalent among depressives. However, as depression is a complex disorder in which minor changes of many genes as well as environmental factors (including epigenetic programming) play a causal role and determine the phenotype, the use of mice with single gene mutations needs to be critically discussed when attempting to create a genetic animal model of depression.

Animals↗