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Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C subunit of the voltage-gated L-type calcium channel Ca v 1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Ca v 1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene × environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Ca v 1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Ca v 1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.

Response to antidepressant treatment in major depressive disorder (MDD) cannot be predicted currently, leading to uncertainty in medication selection, increasing costs, and prolonged suffering for many patients. Despite tremendous efforts in identifying response-associated genes in large genome-wide association studies, the results have been fairly modest, underlining the need to establish conceptually novel strategies. For the identification of transcriptome signatures that can distinguish between treatment responders and nonresponders, we herein submit a novel animal experimental approach focusing on extreme phenotypes. We utilized the large variance in response to antidepressant treatment occurring in DBA/2J mice, enabling sample stratification into subpopulations of good and poor treatment responders to delineate response-associated signature transcript profiles in peripheral blood samples. As a proof of concept, we translated our murine data to the transcriptome data of a clinically relevant human cohort. A cluster of 259 differentially regulated genes was identified when peripheral transcriptome profiles of good and poor treatment responders were compared in the murine model. Differences in expression profiles from baseline to week 12 of the human orthologues selected on the basis of the murine transcript signature allowed prediction of response status with an accuracy of 76% in the patient population. Finally, we show that glucocorticoid receptor (GR)-regulated genes are significantly enriched in this cluster of antidepressant-response genes. Our findings point to the involvement of GR sensitivity as a potential key mechanism shaping response to antidepressant treatment and support the hypothesis that antidepressants could stimulate resilience-promoting molecular mechanisms. Our data highlight the suitability of an appropriate animal experimental approach for the discovery of treatment response-associated pathways across species.

Anxiety disorders constitute a major disease and social burden worldwide; however, many questions concerning the underlying molecular mechanisms still remain open. Besides the involvement of the major excitatory (glutamate) and inhibitory (gamma aminobutyric acid (GABA)) neurotransmitter circuits in anxiety disorders, the stress system has been directly implicated in the pathophysiology of these complex mental illnesses. The glucocorticoid receptor (GR) is the major receptor for the stress hormone cortisol (corticosterone in rodents) and is widely expressed in excitatory and inhibitory neurons, as well as in glial cells. However, currently it is unknown which of these cell populations mediate GR actions that eventually regulate fear- and anxiety-related behaviors. In order to address this question, we generated mice lacking the receptor specifically in forebrain glutamatergic or GABAergic neurons by breeding GR flox/flox mice to Nex-Cre or Dlx5/6-Cre mice, respectively. GR deletion specifically in glutamatergic, but not in GABAergic, neurons induced hypothalamic-pituitary-adrenal axis hyperactivity and reduced fear- and anxiety-related behavior. This was paralleled by reduced GR-dependent electrophysiological responses in the basolateral amygdala (BLA). Importantly, viral-mediated GR deletion additionally showed that fear expression, but not anxiety, is regulated by GRs in glutamatergic neurons of the BLA. This suggests that pathological anxiety likely results from altered GR signaling in glutamatergic circuits of several forebrain regions, while modulation of fear-related behavior can largely be ascribed to GR signaling in glutamatergic neurons of the BLA. Collectively, our results reveal a major contribution of GRs in the brain's key excitatory, but not inhibitory, neurotransmitter system in the regulation of fear and anxiety behaviors, which is crucial to our understanding of the molecular mechanisms underlying anxiety disorders.

It has been demonstrated that the neuropeptide oxytocin (OT) attenuates oxidative stress and inflammation in macrophages. In the current study, we examined the role of inflammation on the expression of the oxytocin receptor (OXTR). We hypothesized that OXTR expression is increased during the inflammation through a nuclear factor-κB (NF-κB)-mediated pathway, thus responding as an acute-phase protein. Inflammation was induced by treating macrophages (human primary, THP-1, and murine) with lipopolysaccharide (LPS) and monitored by expression of IL-6. Expression of OXTR and vasopressin receptors was assessed by qPCR, and OXTR expression was confirmed by immunoblotting. Inflammation upregulated OXTR transcription 10- to 250-fold relative to control in THP-1 and human primary macrophages and increased OXTR protein expression. In contrast, vasopressin receptor-2 mRNA expression was reduced following LPS treatment. Blocking NF-κB activation prevented the increase in OXTR transcription. OT treatment of control cells and LPS-treated cells increased ERK1/2 phosphorylation, demonstrating activation of the OXTR/G αq/11 signaling pathway. OT activation of OXTR reduced secretion of IL-6 in LPS-activated macrophages. Collectively, these findings suggest that OXTR is an acute-phase protein and that its increased expression is regulated by NF-κB and functions to attenuate cellular inflammatory responses in macrophages., (Copyright © 2017 the American Physiological Society.)

Alterations of postsynaptic density (PSD)95-complex proteins in schizophrenia ostensibly induce deficits in synaptic plasticity, the molecular process underlying cognitive functions. Although some PSD95-complex proteins have been previously examined in the hippocampus in schizophrenia, the status of other equally important molecules is unclear. This is especially true in the cornu ammonis (CA)1 hippocampal subfield, a region that is critically involved in the pathophysiology of the illness. We thus performed a quantitative immunoblot experiment to examine PSD95 and several of its associated proteins in the CA1 region, using post mortem brain samples derived from schizophrenia subjects with age-, sex-, and post mortem interval-matched controls (n=20/group). Our results indicate a substantial reduction in PSD95 protein expression (-61.8%). Further analysis showed additional alterations to the scaffold protein Homer1 (Homer1a: +42.9%, Homer1b/c: -24.6%), with a twofold reduction in the ratio of Homer1b/c:Homer1a isoforms (P=0.011). Metabotropic glutamate receptor 1 (mGluR1) protein levels were significantly reduced (-32.7%), and Preso, a protein that supports interactions between Homer1 or PSD95 with mGluR1, was elevated (+83.3%). Significant reduction in synaptophysin (-27.8%) was also detected, which is a validated marker of synaptic density. These findings support the presence of extensive molecular abnormalities to PSD95 and several of its associated proteins in the CA1 region in schizophrenia, offering a small but significant step toward understanding how proteins in the PSD are altered in the schizophrenia brain, and their relevance to overall hippocampal and cognitive dysfunction in the illness.

Psychotropic medications target glycogen synthase kinase 3β (GSK3β), but the functional integration with other factors relevant for drug efficacy is poorly understood. We discovered that the suggested psychiatric risk factor FK506 binding protein 51 (FKBP51) increases phosphorylation of GSK3β at serine 9 (pGSK3β(S9)). FKBP51 associates with GSK3β mainly through its FK1 domain; furthermore, it also changes GSK3β's heterocomplex assembly by associating with the phosphatase PP2A and the kinase cyclin-dependent kinase 5. FKBP51 acts through GSK3β on the downstream targets Tau, β-catenin and T-cell factor/lymphoid enhancing factor (TCF/LEF). Lithium and the antidepressant (AD) paroxetine (PAR) functionally synergize with FKBP51, as revealed by reporter gene and protein association analyses. Deletion of FKBP51 blunted the PAR- or lithium-induced increase in pGSK3β(S9) in cells and mice and attenuated the behavioral effects of lithium treatment. Clinical improvement in depressive patients was predicted by baseline GSK3β pathway activity and by pGSK3β(S9) reactivity to ex vivo treatment of peripheral blood mononuclear lymphocytes with lithium or PAR. In sum, FKBP51-directed GSK3β activity contributes to the action of psychotropic medications. Components of the FKBP51-GSK3β pathway may be useful as biomarkers predicting AD response and as targets for the development of novel ADs.

Major depression is a multifactorial disease, involving both environmental and genetic risk factors. Recently, SLC6A15 - a neutral amino acid transporter mainly expressed in neurons - was proposed as a new candidate gene for major depression and stress vulnerability. Risk allele carriers for a single nucleotide polymorphism (SNP) in a SLC6A15 regulatory region display altered hippocampal volume, glutamate levels, and hypothalamus-pituitary-adrenal axis activity, all markers associated with major depression. Despite this genetic link between SLC6A15 and depression, its functional role with regard to the development and maintenance of depressive disorder is still unclear. The aim of the current study was therefore to characterize the role of mouse slc6a15 in modulating brain function and behavior, especially in relation to stress as a key risk factor for the development of mood disorders. We investigated the effects of slc6a15 manipulation using two mouse models, a conventional slc6a15 knock-out mouse line (SLC-KO) and a virus-mediated hippocampal slc6a15 overexpression (SLC-OE) model. Mice were tested under basal conditions and following chronic social stress. We found that SLC-KO animals displayed a similar behavioral profile to wild-type littermates (SLC-WT) under basal conditions. Interestingly, following chronic social stress SLC-KO animals showed lower levels of anxiety- and depressive-like behavior compared to stressed WT littermates. In support of these findings, SLC-OE animals displayed increased anxiety-like behavior already under basal condition. We also provide evidence that GluR1 expression in the dentate gyrus, but not GluR2 or NR1, are regulated by slc6a15 expression, and may contribute to the difference in stress responsiveness observed between SLC-KO and SLC-WT animals. Taken together, our data demonstrate that slc6a15 plays a role in modulating emotional behavior, possibly mediated by its impact on glutamatergic neurotransmission.

Anxiety-related psychiatric disorders represent one of the largest health burdens worldwide. Single nucleotide polymorphisms of the FK506 binding protein 51 (FKBP51) gene have been repeatedly associated with anxiety-related disorders and stress sensitivity. Given the intimate relationship of stress and anxiety, we hypothesized that amygdala FKBP51 may mediate anxiety-related behaviors. Mimicking the stress effect by specifically overexpressing FKBP51 in the basolateral amygdala (BLA) or central amygdala resulted in increased anxiety-related behavior, respectively. In contrast, application of a highly selective FKBP51 point mutant antagonist, following FKBP51(mut) BLA-overexpression, reduced the anxiogenic phenotype. We subsequently tested a novel FKBP51 antagonist, SAFit2, in wild-type mice via BLA microinjections, which reduced anxiety-related behavior. Remarkably, the same effect was observed following peripheral administration of SAFit2. To our knowledge, this is the first in vivo study using a specific FKBP51 antagonist, thereby unraveling the role of FKBP51 and its potential as a novel drug target for the improved treatment of anxiety-related disorders., (Copyright © 2015 the authors 0270-6474/15/359007-10$15.00/0.)

Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Understanding the molecular mechanisms that promote stress resilience might open up new therapeutic avenues to prevent stress-related disorders. We recently characterized a stress and glucocorticoid-regulated gene, down-regulated in renal cell carcinoma - DRR1 (Fam107A). DRR1 is expressed in the mouse brain; it is up-regulated by stress and glucocorticoids and modulates neuronal actin dynamics. In the adult mouse, DRR1 was shown to facilitate specific behaviors which might be protective against some of the deleterious consequences of stress exposure: in the hippocampal CA3 region, DRR1 improved cognitive performance whereas in the septum, it specifically increased social behavior. Therefore DRR1 was suggested as a candidate protein promoting stress-resilience. Fam107B (family with sequence similarity 107, member B) is the unique paralog of DRR1, and both share high sequence similarities, predicted glucocorticoid response elements, heat-shock induction and tumor suppressor properties. So far, the role of Fam107B in the central nervous system was not studied. The aim of the present investigation, therefore, was to analyze whether Fam107B and DRR1 display comparable mRNA expression patterns in the brain and whether both are modulated by stress and glucocorticoids. Spatio-temporal mapping of Fam107B mRNA expression in the embryonic and adult mouse brain, by means of in situ hybridization, showed that Fam107B was expressed during embryogenesis and in the adulthood, with particularly high and specific expression in the forming telencephalon suggestive of an involvement in corticogenesis. In the adult mouse, expression was restricted to neurogenic niches, like the dentate gyrus. In contrast to DRR1, Fam107B mRNA expression failed to be modulated by glucocorticoids and social stress in the adult mouse. In summary, Fam107B and DRR1 show different spatio-temporal expression patterns in the central nervous system, suggesting at least partially different functional roles in the brain, and where the glucocorticoid receptor (GR)-induced regulation appears to be a unique property of DRR1., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a, and chronic administration of the mGluR5 inverse agonist CTEP (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine) on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated and, accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 knockout (KO) mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, whereas overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.

Background: FK506 binding protein 51 (FKBP51) is an Hsp90 co-chaperone and regulator of the glucocorticoid receptor, and consequently of stress physiology. Clinical studies suggest a genetic link between FKBP51 and antidepressant response in mood disorders; however, the underlying mechanisms remain elusive. The objective of this study was to elucidate the role of FKBP51 in the actions of antidepressants, with a particular focus on pathways of autophagy., Methods and Findings: Established cell lines, primary neural cells, human blood cells of healthy individuals and patients with depression, and mice were treated with antidepressants. Mice were tested for several neuroendocrine and behavioral parameters. Protein interactions and autophagic pathway activity were mainly evaluated by co-immunoprecipitation and Western blots. We first show that the effects of acute antidepressant treatment on behavior are abolished in FKBP51 knockout (51KO) mice. Autophagic markers, such as the autophagy initiator Beclin1, were increased following acute antidepressant treatment in brains from wild-type, but not 51KO, animals. FKBP51 binds to Beclin1, changes decisive protein interactions and phosphorylation of Beclin1, and triggers autophagic pathways. Antidepressants and FKBP51 exhibited synergistic effects on these pathways. Using chronic social defeat as a depression-relevant stress model in combination with chronic paroxetine (PAR) treatment revealed that the stress response, as well as the effects of antidepressants on behavior and autophagic markers, depends on FKBP51. In human blood cells of healthy individuals, FKBP51 levels correlated with the potential of antidepressants to induce autophagic pathways. Importantly, the clinical antidepressant response of patients with depression (n = 51) could be predicted by the antidepressant response of autophagic markers in patient-derived peripheral blood lymphocytes cultivated and treated ex vivo (Beclin1/amitriptyline: r = 0.572, p = 0.003; Beclin1/PAR: r = 0.569, p = 0.004; Beclin1/fluoxetine: r = 0.454, p = 0.026; pAkt/amitriptyline: r =  -0.416, p = 0.006; pAkt/PAR: r =  -0.355, p = 0.021; LC3B-II/PAR: r = 0.453, p = 0.02), as well as by the lymphocytic expression levels of FKBP51 (r = 0.631, p<0.0001), pAkt (r =  -0.515, p = 0.003), and Beclin1 (r = 0.521, p = 0.002) at admission. Limitations of the study include the use of male mice only and the relatively low number of patients for protein analyses., Conclusions: To our knowledge, these findings provide the first evidence for the molecular mechanism of FKBP51 in priming autophagic pathways; this process is linked to the potency of at least some antidepressants. These newly discovered functions of FKBP51 also provide novel predictive markers for treatment outcome, consistent with physiological and potential clinical relevance. Please see later in the article for the Editors' Summary.

Understanding the molecular mechanisms by which stress is translated into changes in complex behavior may help to identify novel treatment strategies for stress-associated psychiatric disorders. The tumor suppressor gene down-regulated in renal cell carcinoma 1 (DRR1) was recently characterized as a new molecular link between stress, synaptic efficacy and behavioral performance, most likely through its ability to modulate actin dynamics. The lateral septum is one of the brain regions prominently involved in the stress response. This brain region features high DRR1 expression in adult mice, even under basal conditions. We therefore aimed to characterize and dissect the functional role of septal DRR1 in modulating complex behavior. DRR1 protein expression was shown to be expressed in both neurons and astrocytes of the lateral septum of adult mice. Septal DRR1 mRNA expression increased after acute defeat stress and glucocorticoid receptor activation. To mimic the stress-induced DRR1 increase in the lateral septum of mice, we performed adenovirus-mediated region-specific overexpression of DRR1 and characterized the behavior of these mice. Overexpression of DRR1 in the septal region increased sociability, but did not change cognitive, anxiety-like or anhedonic behavior. The observed changes in social behavior did not involve alterations of the expression of vasopressin or oxytocin receptors, the canonical social neuropeptidergic circuits of the lateral septum. In summary, our data suggest that the stress-induced increase of DRR1 expression in the lateral septum could be a protective mechanism to buffer or counterbalance negative consequences of stress exposure on social behavior., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

While it is known that stress promotes obesity, the effects of stress within an obesogenic context are not so clear and molecular targets at the interface remain elusive. The FK506-binding protein 51 (FKBP51, gene: Fkbp5) has been identified as a target gene implicated in the development of stress-related psychiatric disorders and is a possible candidate for involvement in stress and metabolic regulation. The aims of the current study are to investigate the interaction between chronic stress and an obesogenic context and to additionally examine whether FKBP51 is involved in this interaction. For this purpose, male C57BL/6 mice were exposed to a high-fat diet for 8 weeks before being challenged with chronic social defeat stress. Herein, we demonstrate that chronic stress induces hypophagia and weight loss, ultimately improving features arising from an obesogenic context, including glucose tolerance and levels of insulin and leptin. We show that Fkbp5 expression is responsive to diet and stress in the hypothalamus and hippocampus respectively. Furthermore, under basal conditions, higher levels of hypothalamic Fkbp5 expression were related to increased body weight gain. Our data indicate that Fkbp5 may represent a novel target in metabolic regulation., (© 2014 Society for Endocrinology.)

Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform long-term effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse CRH receptor 1 (Crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows a better understanding of the currently reported genes × environment interactions of early trauma and CRHR1 in humans. We identified 2 main haplotype variants in the mouse Crhr1 locus that modulate the long-term effects of ACSS on basal hypothalamic-pituitary-adrenal axis activity. This effect is likely mediated by higher levels of CRHR1, because Crhr1 mRNA expression and CRHR1 binding were enhanced in risk haplotype carriers. Furthermore, a CRHR1 receptor antagonist normalized these long-term effects. Deep sequencing of the Crhr1 locus in CD1 mice revealed a large number of linked single-nucleotide polymorphisms with some located in important regulatory regions, similar to the location of human CRHR1 variants implicated in modulating gene × stress exposure interactions. Our data support that the described gene × stress exposure interaction in this animal model is based on naturally occurring genetic variations in the Crhr1 gene associated with enhanced CRHR1-mediated signaling. Our results suggest that patients with a specific genetic predisposition in the CRHR1 gene together with an exposure to chronic stress may benefit from a treatment selectively antagonizing CRHR1 hyperactivity.

Chronic stress is one of the predominant environmental risk factors for a number of psychiatric disorders, particularly for major depression. Different hypotheses have been formulated to address the interaction between early and adult chronic stress in psychiatric disease vulnerability. The match/mismatch hypothesis of psychiatric disease states that the early life environment shapes coping strategies in a manner that enables individuals to optimally face similar environments later in life. We tested this hypothesis in female Balb/c mice that underwent either stress or enrichment early in life and were in adulthood further subdivided in single or group housed, in order to provide aversive or positive adult environments, respectively. We studied the effects of the environmental manipulation on anxiety-like, depressive-like and sociability behaviors and gene expression profiles. We show that continuous exposure to adverse environments (matched condition) is not necessarily resulting in an opposite phenotype compared to a continuous supportive environment (matched condition). Rather, animals with mismatched environmental conditions behaved differently from animals with matched environments on anxious, social and depressive like phenotypes. These results further support the match/mismatch hypothesis and illustrate how mild or moderate aversive conditions during development can shape an individual to be optimally adapted to similar conditions later in life., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Psychiatric disorders such as depressive disorders and posttraumatic stress disorder are a major disease burden worldwide and have a higher incidence in women than in men. However, the underlying mechanism responsible for the sex-dependent differences is not fully understood. Besides environmental factors such as traumatic life events or chronic stress, genetic variants contribute to the development of such diseases. For instance, variations in the gene encoding the FK506 binding protein 51 (FKBP51) have been repeatedly associated with mood and anxiety. FKBP51 is a negative regulator of the glucocorticoid receptor and thereby of the hypothalamic-pituitary-adrenal axis that also interacts with other steroid hormone receptors such as the progesterone and androgen receptors. Thus, the predisposition of women to psychiatric disorders and the interaction of female hormones with FKBP51 and the glucocorticoid receptor implicate a possible difference in the regulation of the hypothalamic-pituitary-adrenal axis in female FKBP51 knockout (51KO) mice. Therefore, we investigated neuroendocrine, behavioural and physiological alterations relevant to mood disorders in female 51KO mice. Female 51KOs and wild type littermates were subjected to various behavioural tests, including the open field, elevated plus maze and forced swim test. The neuroendocrine profile was investigated under basal conditions and in response to an acute stressor. Furthermore, we analysed the mRNA expression levels of the glucocorticoid receptor and corticotrophin release hormone in different brain regions. Overall, female 51KO mice did not display any overt behavioural phenotype under basal conditions, but showed a reduced basal hypothalamic-pituitary-adrenal axis activity, a blunted response to, and an enhanced recovery from, acute stress. These characteristics strongly overlap with previous studies in male 51KO mice indicating that FKBP51 shapes the behavioural and neuroendocrine phenotype independent of the sex of the individual.

Loss of motivation and learning impairments are commonly accepted core symptoms of psychiatric disorders such as depression and schizophrenia. Reward-motivated learning is dependent on the hippocampal formation but the molecular mechanisms that lead to functional incentive motivation in this brain region are still largely unknown. Recent evidence implicates neurotransmission via metabotropic glutamate receptors and Homer1, their interaction partner in the postsynaptic density, in drug addiction and motivational learning. As previous reports mainly focused on the prefrontal cortex and the nucleus accumbens, we now investigated the role of hippocampal Homer1 in operant reward learning in the present study. We therefore tested either Homer1 knockout mice or mice that overexpress Homer1 in the hippocampus in an operant conditioning paradigm. Our results show that deletion of Homer1 leads to a diverging phenotype that either displays an inability to perform the task or outstanding hyperactivity in both learning and motivational sessions. Due to the apparent bimodal distribution of this phenotype, the overall effect of Homer1 deletion in this paradigm is not significantly altered. Overexpression of hippocampal Homer1 did not lead to a significantly altered learning performance in any stage of the testing paradigm, yet may subtly contribute to emerging motivational deficits. Our results indicate an involvement of Homer1-mediated signaling in the hippocampus in motivation-based learning tasks and encourage further investigations regarding the specific molecular underpinnings of the phenotypes observed in this study. We also suggest to cautiously interpret the results of this and other studies regarding the phenotype following Homer1 manipulations in animals, since their behavioral phenotype appears to be highly diverse. Future studies would benefit from larger group sizes that would allow splitting the experimental groups in responders and non-responders.

Stress impairs cognition via corticotropin-releasing hormone receptor 1 (CRHR1), but the molecular link between abnormal CRHR1 signaling and stress-induced cognitive impairments remains unclear. We investigated whether the cell adhesion molecule nectin-3 is required for the effects of CRHR1 on cognition and structural remodeling after early-life stress exposure. Postnatally stressed adult mice had decreased hippocampal nectin-3 levels, which could be attenuated by CRHR1 inactivation and mimicked by corticotropin-releasing hormone (CRH) overexpression in forebrain neurons. Acute stress dynamically reduced hippocampal nectin-3 levels, which involved CRH-CRHR1, but not glucocorticoid receptor, signaling. Suppression of hippocampal nectin-3 caused spatial memory deficits and dendritic spine loss, whereas enhancing hippocampal nectin-3 expression rescued the detrimental effects of early-life stress on memory and spine density in adulthood. Our findings suggest that hippocampal nectin-3 is necessary for the effects of stress on memory and structural plasticity and indicate that the CRH-CRHR1 system interacts with the nectin-afadin complex to mediate such effects.

In recent years, the glutamatergic system has been implicated in the development and treatment of psychiatric disorders. Glutamate signaling is processed by different receptors, including metabotropic glutamate receptors (mGluRs), which in turn interact with the scaffolding protein Homer1 to modulate downstream Ca(2+) signaling. Stress is a major risk factor for the incidence of psychiatric diseases, yet acute stress episodes may have diverging effects on individuals. Cognitive impairments have often been shown to occur after episodes of stress, however the specific role of mGluR5/Homer1 signaling in the interaction of stress and cognition has not yet been elucidated. In this study we show that a single episode of social defeat stress is sufficient to specifically induce cognitive impairments in mice 8 h after the stressor without affecting the animals' locomotion or anxiety levels. We also demonstrate that Homer1b/c levels as well as mGluR5/Homer1b/c interactions in the dorsal hippocampus are reduced up to 8 h after stress. Blockade of mGluR5 during the occurrence of social stress was able to rescue the cognitive impairments. In addition, a specific overexpression of Homer1b/c in the dorsal hippocampus also reversed the behavioral phenotype, indicating that both mGluR5 and Homer1b/c play a crucial role in the mediation of the stress effects. In summary, we could demonstrate that stress induces a cognitive deficit that is likely mediated by mGluR5/Homer1 signaling in the hippocampus. These findings help to reveal the underlying effects of cognitive impairments in patients suffering from stress-related psychiatric disorders.

Aversive life events represent one of the main risk factors for the development of many psychiatric diseases, but the interplay between environmental factors and genetic predispositions is still poorly understood. One major finding in many depressed patients is an impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The negative feedback loop of the HPA axis is mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The co-chaperones FK506-binding protein 51 (FKBP51) and FK506-binding protein 52 (FKBP52) are components of the heat shock protein 90-receptor-heterocomplex and are functionally divergent regulators of both receptors. Here, we characterized heterozygous Fkbp52 knockout (Fkbp52(+/-)) mice under basal or chronic social defeat stress (CSDS) conditions with regard to physiological, neuroendocrine, behavioral and mRNA expression alterations. Fkbp52(+/-) mice displayed symptoms of increased stress sensitivity in a subset of behavioral and neuroendocrine parameters. These included increased anxiety-related behavior in the elevated plus-maze and an enhanced neuroendocrine response to a forced swim test (FST), possibly mediated by reduced GR sensitivity. At the same time, Fkbp52(+/-) mice also demonstrated signs of stress resilience in other behavioral and neuroendocrine aspects, such as reduced basal corticosterone levels and more active stress-coping behavior in the FST following CSDS. These contrasting results are in line with previous reports showing that FKBP52 is not involved in all branches of GR signaling, but rather acts in a gene-specific manner to regulate GR transcriptional activation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Various clinical studies have identified FK506-binding protein 51 (FKBP51) as a target gene involved in the development of psychiatric disorders such as depression. Furthermore, FKBP51 has been shown to affect glucocorticoid receptor signaling by sensitivity modulation and it is implicated in stress reactivity as well as in molecular mechanisms of stress vulnerability and resilience. We investigated the physiological, behavioral, and neuroendocrine parameters in an established chronic stress model both directly after stress and after a recovery period of 3 weeks and also studied the efficacy of paroxetine in this model. We then examined FKBP51 mRNA levels in the dorsal and ventral part of the hippocampus and correlated the expression to behavioral and endocrine parameters. We show robust chronic stress effects in physiological, behavioral, and neuroendocrine parameters, which were only slightly affected by paroxetine treatment. On the contrary, paroxetine led to a disruption of the neuroendocrine system. FKBP51 expression was significantly increased directly after the stress period and correlated with behavioral and neuroendocrine parameters. Taken together, we were able to further elucidate the role of FKBP51 in the mechanisms of stress resilience and vulnerability, especially with respect to behavioral and neuroendocrine parameters. These findings strongly support the concept of FKBP51 as a marker for glucocorticoid receptor sensitivity and its involvement in the development of psychiatric disorders.

Chronic stress is increasingly considered to be a main risk factor for the development of a variety of psychiatric diseases such as depression. This is further supported by an impaired negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which has been observed in the majority of depressed patients. The effects of glucocorticoids, the main hormonal endpoint of the HPA axis, are mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The FK506-binding protein 51 (FKBP5), a co-chaperone of the Hsp90 and component of the chaperone-receptor heterocomplex, has been shown to reduce ligand sensitivity of the GR. This study aimed to investigate the function of FKBP5 as a possible mediator of the stress response system and its potential role in the development of stress-related diseases. Therefore, we assessed whether mice lacking the gene encoding FKBP5 (51KO mice) were less vulnerable to the adverse effects of three weeks of chronic social defeat stress. Mice were subsequently analyzed with regards to physiological, neuroendocrine, behavioral and mRNA expression alterations. Our results show a less vulnerable phenotype of 51KO mice with respect to physiological and neuroendocrine parameters compared to wild-type animals. 51KO mice demonstrated lower adrenal weights and basal corticosterone levels, a diminished response to a novel acute stimulus and an enhanced recovery, as well as more active stress-coping behavior. These results suggest an enhanced negative glucocorticoid feedback within the HPA axis of 51KO mice, possibly modulated by an increased sensitivity of the GR. This article is part of a Special Issue entitled 'Anxiety and Depression'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The incidence of chronic stress is frequently related to the development of psychiatric disorders like depression. The hypothalamic-pituitary-adrenal (HPA) axis is a major physiological system that mediates the stress response. Tight HPA axis regulation through negative feedback mechanisms is essential for health and environmental adaptation. This feedback regulation acts in part through the glucocorticoid receptor (GR) on several organizational levels, including the pituitary, the hypothalamus and the hippocampus. However, the precise role of the different anatomical structures, specifically the pituitary, in HPA axis regulation is yet largely unknown. Here, we show that a conditional pituitary GR knockout is not necessarily detrimental for the animal's ability to cope with chronic stress situations. Mice with a deletion of the GR at the pituitary (GR(POMCCre)) were subjected to 3 weeks of chronic social defeat stress. We analyzed both the behavioral and neuroendocrine phenotype as well as the central nervous system expression of genes involved in HPA axis function in these animals. Our results show a more resilient phenotype of GR(POMCCre) mice with respect to anxiety-related behavior and neuroendocrine parameters compared to stressed wild type animals. In light of the previously reported high corticosterone levels during postnatal development in GR(POMCCre) mice, our findings suggest that adverse early life events may have beneficial developmental effects on the organism to improve stress coping later in life., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Chronic granulocytic leukemia (CGL) is associated with a reciprocal translocation between chromosomes 9 and 22. The breakpoint sites on chromosome 22 are clustered in a limited region known as the major breakpoint cluster region (Mbcr). This region is approximately 5.8 Kb long and can be arbitrarily subdivided into five zones (1 through 5 from the 5' towards the 3' end) as defined by the particular sites of three restriction endonucleases. Using Southern blot analysis with two DNA probes, one spanning both the 5' and 3' regions of the Mbcr while the other only the 3' region, we mapped the precise location of the chromosomal breakpoints within the Mbcr in 62 patients with CGL and examined possible clinical correlations. There were 39 patients with 5' breakpoints (zones 1-3) and 23 patients with 3' breakpoints (zones 4 and 5). We found no correlation between the clinical phase of the disease at last followup and breakpoint distributions. The distributions of chronic phase duration (CPD) and survival were similar between patients with 5' breakpoints (median CPD = 4.0 years) and those with 3' breakpoints (median CPD = 5.2 years). Presenting clinical features and the rates of lymphoblastic transformation were also similar among the subgroups. Our data suggest that the precise location of the breakpoint within the Mbcr in CGL may not have clinical relevance.

Ten years have now passed since the American Cancer Society/National Cancer Institute sponsored Breast Cancer Detection Demonstration Projects (BCDDP) started to evaluate the use of mammography, physical examination, thermography, and breast self-examination in screening women for the presence of unsuspected breast cancer. Criteria have been developed to evaluate population screening as an approach to cancer control and breast cancer screening techniques. Combined physical examination and mammography have been particularly successful in detecting early breast cancer. Although the number of screening programs for breast cancer has increased in the past decade, real progress has been surprisingly slow and the issues in breast cancer screening have proved to be subtle and complex.