Recent studies suggest that both common and rare variants are involved in the genetic risk of schizophrenia. Using a Cochran-Mantel-Haenszel (CMH) adjusted meta-analysis in 36,676 schizophrenia patients and 48,331 healthy controls from 24 independent samples, we identify the microduplications at 16p11.2 locus (29.6–30.2 Mb, hg19) to be strongly associated with the illness (P value < 2.2 × 10− 16, CHM-adjusted OR = 10.79). The frequency of this microduplication is significantly higher in schizophrenia patients (0.267%) comparing to healthy controls (0.025%). Further, using the largest published genome-wide association study (GWAS) data (36,989 cases and 113,075 controls), we show that common variants at the 16p11.2 locus are also significantly associated with schizophrenia (e.g., rs12691307, P value = 4.55 × 10− 11, OR = 1.073). These results confirm the link between 16p11.2 genomic region and genetic risk of schizophrenia.

Exposure to early-life stress (ELS) may heighten the risk for psychopathology at adulthood. Here, in order to identify common genes that may keep the memory of ELS through changes in their methylation status, we intersected methylome analyses performed in different tissues and time points in rats, non-human primates and humans, all characterized by ELS. We identified Ankyrin-3 ( Ank3 ), a scaffolding protein with a strong genetic association for psychiatric disorders, as a gene persistently affected by stress exposure. In rats, Ank3 methylation and mRNA changes displayed a specific temporal profile during the postnatal development. Moreover, exposure to prenatal stress altered the interaction of ankyrin-G, the protein encoded by Ank3 enriched in the post-synaptic compartment, with PSD95. Notably, to model in humans a gene by early stress interplay on brain phenotypes during cognitive performance, we demonstrated an interaction between functional variation in Ank3 gene and obstetric complications on working memory in healthy adult subjects. Our data suggest that alterations of Ank3 expression and function may contribute to the effects of ELS on the development of psychiatric disorders.

Prenatal maternal infection represents a risk factor for the development of psychopathologic conditions later in life. Clinical evidence is also supported by animal models in which the vulnerability to develop a schizophrenic-like phenotype likely originates from inflammatory processes as early as in the womb. Prenatal immune challenge, for example, induces a variety of long-term behavioral alterations in mice, such as deficits in recognition and spatial working memory, perseverative behaviors and social impairments, which are relevant to different symptom clusters of schizophrenia. Here, we investigated the modulation of GABAergic markers in the dorsal and ventral hippocampus of adult mice exposed to late prenatal immune challenge with the viral mimetic Poly(I:C) (polyriboinosinic-polyribocytidilic-acid) at gestational day 17, and we evaluated the ability of chronic treatment with the multi-receptor antipsychotic lurasidone to modulate the alterations produced by maternal infection. Poly(I:C) mice show a significant reduction of key GABAergic markers, such as GAD67 and parvalbumin, specifically in the dorsal hippocampus, which were normalized by chronic lurasidone administration. Moreover, chronic drug administration increases the expression of the pool of brain derived neurotrophic factor (BDNF) transcripts with the long 3'-UTR as well as the levels of mature BDNF protein in the synaptosomal compartment, selectively in dorsal hippocampus. All in all, our findings demonstrate that lurasidone is effective in ameliorating molecular abnormalities observed in Poly(I:C) mice, providing further support to the neuroplastic properties of this multi-receptor antipsychotic drug.

Cranial radiation therapy (CRT) is an effective treatment for brain tumors; however, it also causes brain injuries. The pediatric brain is considered especially vulnerable compared to the adult brain; thus, brain injuries caused by CRT may severely affect their quality of life. In this study, we determined the neuroprotective effects of nasal oxytocin administration following cranial radiation in mice. We investigated the cognitive behavior of mice (novel object recognition test and novel object location test), phosphorylated histone H2AX (γ-H2AX) and K+-Cl− transporter (KCC2) by immunohistochemical analysis of the hippocampal sections, and neuronal cells by immunocytochemistry after radiation and oxytocin administration. We found that the number of γ-H2AX foci was increased, and the surface signal intensity of KCC2 immunofluorescence was decreased in cells that were irradiated with X-rays (1.5 Gy, for three consecutive days) compared with cells that were not. Furthermore, using MQAE, we found that the intracellular chloride ion concentration was downregulated in oxytocin-treated cells by increasing surface KCC2 expression. These results indicate that nasal oxytocin administration after cranial irradiation attenuates cognitive dysfunction in mice and exerts multifaceted neuroprotective effects on DNA damage and maintains chloride ion concentration in neuronal cells.

Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the underlying molecular mechanisms are still poorly understood. An important player involved these processes is the Serum Glucocorticoid kinase-1 (SGK-1), which is not only a mediator of stress, but also of inflammatory related pathways. I will show the impact of early life stressful events (ELS) on SGK-1 pathway, and I will present data in animal models of ELS and also in the blood of subjects with history childhood trauma. SGK1 gene expression is higher in the hippocampus of adult rats exposed to a prenatal stress paradigm (+48%, p < 0.005) versus controls. Importantly, when adult animals were exposed to an acute stress, I found that stress causes an increase in SGK1 levels in control animals (+41%, p < 0.005), and that this effect was more pronounced in animals previously exposed to prenatal stress (+138%, p < 0.005), suggesting that the system has been sensitised early in life to be more reactive to further stressful in the adulthood. I have also observed higher SGK1 mRNA levels in subjects with a history of trauma as compared to those without this experiences (+45% p < 0.05), and also in depressed patients (+30%, p < 0.05) versus controls. This data suggests that stress early in life induces changes in SGK1 system that persist over time and may be responsible for an increased vulnerability to psychopathology in the adulthood.

Morc1 gene has recently been identified by a DNA methylation and genome-wide association study as a candidate gene for major depressive disorder related to early life stress in rodents, primates and humans. So far, no transgenic animal model has been established to validate these findings on a behavioral level. In the present study, we examined the effects of a Morc1 loss of function mutation in female C57BL/6N mice on behavioral correlates of mood disorders like the Forced Swim Test, the Learned Helplessness Paradigm, O-Maze and Dark-Light-Box. We could show that Morc1(-/-) mice display increased depressive-like behavior whereas no behavioral abnormalities regarding locomotor activity or anxiety-like behavior were detectable. CORT plasma levels did not differ significantly between Morc1(-/-) mice and their wildtype littermates, yet - surprisingly - total Bdnf mRNA-levels in the hippocampus were up-regulated in Morc1(-/-) animals. Although further work would be clarifying, Morc1(-/-) mice seem to be a promising epigenetically validated mouse model for depression associated with early life stress. (C) 2015 Elsevier B.V. All rights reserved.

The purpose of this study is to examine the prevalence of affective temperaments between clinically unaffected relatives of bipolar patients and secondarily to investigate the impact of these “subaffective” forms on their quality of life (QoL).The study was performed in seven sites across Argentina. We administered the scales TEMPS-A and Quality of Life Index to a sample of 114 non-ill first degree relatives of bipolar disorder patients (“cases”) and 115 comparison subjects without family history of affective illness (“controls”). We used The Mood Disorder Questionnaire to rule out clinical bipolarity.Mean scores on all TEMPS-A subscales were significantly higher in cases, except for hyperthymia. The prevalence of affective temperaments, according to Argentinean cut-off points, was also higher, with statistical significance for cyclothymic and anxious temperaments. Regarding QoL, we found no significant differences between both groups, except for interpersonal functioning, which was better in controls. A detailed subanalysis showed significant effects of QoL domains for all temperaments, except for the hyperthymic.We used self-report measures. A larger sample size would have provided us greater statistical power for certain analyses.Our findings support the concept of a spectrum of subthreshold affective traits or temperaments – especially for the cyclothymic and anxious – in bipolar pedigrees. We further demonstrated that, except for the hyperthymic, quality of life was affected by these temperaments in “clinically well” relatives. Overall, our data are compatible with the “endophenotype” and “subaffective” theses for affective temperaments.

Exposure to early adversities represents a major risk factor for psychiatric disorders. We have previously shown that exposure to prenatal stress (PNS) in rats alters the developmental expression of brain-derived neurotrophic factor (Bdnf) with a specific temporal profile. However, exposure to early-life stress is known to alter the ability to cope with challenging events later in life, which may contribute to the enhanced vulnerability to stress-related disorders. Since Bdnf is also an important player for activity-dependent plasticity, we investigated whether the exposure to PNS in rats could alter Bdnf responsiveness to an acute challenge at adulthood. We found that exposure to PNS produces significant changes in Bdnf responsiveness with brain region- and gender-specific selectivity. Indeed, exposure to an acute stress upregulates Bdnf expression in the prefrontal cortex, but not in the hippocampus, of control animals. Moreover, such modulatory activity is selectively impaired in PNS female rats, an effect that was associated with changes in the modulation of the DNA demethylase Gadd45β. Our results suggest that exposure to PNS may reprogram gene transcription through epigenetic mechanisms reducing the ability to cope under adverse conditions, a trait that is disrupted in psychiatric diseases.

Children exposed to adverse psychosocial experiences, or early parental loss, are at an increased risk for later depression. Preclinical data indicate that epigenetic regulation of gene expression mediates the effects of early life stress (ELS) on adult behavior and health. In addition to stress-responsive systems (glucocorticoids), the expression of neurotrophic factors in the brain may be regulated epigenetically in the context of ELS contributing to mental health, or systemic disease at adulthood. In order to investigate epigenetic changes in target genes involved in the long-term effects of early adversity on psychopathology, we have set up an animal model (rat) of prenatal stress. show that ELS leads to a long-term down-regulation in the expression of target genes, such as the receptor for glucocorticoids and Brain derived neurotrophic factor (BDNF), thus mimicking adult conditions characterizing increased risk for psychopathology. Behavioral and neuroendocrine changes accompanying these differences in gene expression suggest increased stress responsivity, as well as impaired social behavior. Chronic treatment with the antipsychotic lurasidone during adolescence was able to counteract the changes in BDNF expression produced by ELS, preventing the down-regulation of long 3'-UTR BDNF levels that occurred from late adolescence into young adulthood. Furthermore, interaction with a non-stressed rat conspecific ameliorated behavioural dysfunction. data indicate potential therapeutic targets to counteract prenatal stress and suggest that the perinatal environment can act as a potential buffer for stressful conditions occurring around birth. Support: ERA net-NEURON 'Poseidon" and Fondazione Cariplo 2012.

Early life stress (ELS) is associated with increased vulnerability for diseases in later life, including psychiatric disorders. Animal models and human studies suggest that this effect is mediated by epigenetic mechanisms. In humans, epigenetic studies to investigate the influence of ELS on psychiatric phenotypes are limited by the inaccessibility of living brain tissue. Due to the tissue-specific nature of epigenetic signatures, it is impossible to determine whether ELS induced epigenetic changes in accessible peripheral cells, for example, blood lymphocytes, reflect epigenetic changes in the brain. To overcome these limitations, we applied a cross-species approach involving: (i) the analysis of CD34+ cells from human cord blood; (ii) the examination of blood-derived CD3+ T cells of newborn and adolescent nonhuman primates (Macaca mulatta); and (iii) the investigation of the prefrontal cortex of adult rats. Several regions in MORC1 (MORC family CW-type zinc finger 1; previously known as: microrchidia (mouse) homolog) were differentially methylated in response to ELS in CD34+ cells and CD3+ T cells derived from the blood of human and monkey neonates, as well as in CD3+ T cells derived from the blood of adolescent monkeys and in the prefrontal cortex of adult rats. MORC1 is thus the first identified epigenetic marker of ELS to be present in blood cell progenitors at birth and in the brain in adulthood. Interestingly, a gene-set-based analysis of data from a genome-wide association study of major depressive disorder (MDD) revealed an association of MORC1 with MDD.

Psychiatric diseases may often represent the consequence of exposure to adverse events early in life. Accordingly, exposure to stress during gestation in rats has a strong impact on development and can cause long-term abnormalities in adult behavior. Considering that neuronal plasticity has emerged as a major vulnerability element in psychiatric disorders, we investigated the postnatal developmental profile of Brain-Derived Neurotrophic Factor expression (BDNF), an important mediator for long-term functional deterioration associated to mental illness, in male and female rats following exposure to prenatal stress (PNS). Since we found that the majority of alterations became fully manifest at early adulthood, we tried to prevent these abnormalities with an early pharmacological intervention. To address this point, we treated rats during adolescence with the multi-receptor antipsychotic lurasidone, which was proven to be effective in animal models of schizophrenia. Interestingly, we show that lurasidone treatment was able to prevent the reduction of BDNF expression in adult rats that were exposed to PNS.

Combinatory therapy is widely used in psychiatry owing to the possibility that drugs with different mechanisms of action may synergize to improve functions deteriorated in schizophrenia, bipolar disorders, and major depression. While combinatory strategies rely on receptor and synaptic mechanisms, it should also be considered that two drugs may also “interact” on the long-term to determine more robust changes in neuronal plasticity, which represents a downstream target important for functional recovery.

Glutamatergic mechanisms regulate neuronal circuits implicated in mood and anxiety. Emotional disorders as anxiety and depression are particularly difficult to treat during aging and mechanisms underlying emotional disturbances in the brain of the elderly are poorly understood. This may result from the small number of studies investigating these disorders in aged animals. Among glutamate receptors, metabotropic mGlu5 receptors are thought to play an important role, since their pharmacological blockade induces strong anxiolytic effects. However, the implication of mGlu5 in regulating anxiety is not yet completely understood. Here we analyzed both young adult and aged mice lacking mGlu5 receptors, to clarify, if genetic deletion of the receptor induces similar to pharmacological blockade anxiolytic effects. Unexpectedly, mGlu5 receptor knockout (KO) mice showed increased anxiety accentuating with aging. In contrast, young adult mice displayed an anti-depressive-like phenotype that was no longer detectable in aged animals. Our data support important distinct roles of mGlu5 receptors in modulating anxiety and depression during aging.

Objective. The primary goal was to identify risk factors for post-surgical depression in subjects operated on for drug-resistant epilepsy. Secondary goals were to confirm the high rate of depression in subjects suffering from epilepsy (prior to surgery) and to look for first post-surgical depressive episode.Methods. Case series study of 150 subjects surgically treated for partial epilepsy (side of surgery: 72 right, 78 left; site of surgery: 97 Unilobar Temporal, 17 Unilobar Frontal, 14 Posterior, 22 Multilobar). All subjects routinely had three psychiatric evaluations: before surgery (baseline) and at 6 and 12 months after surgery. Psychiatric diagnoses were made according to DSM-IV-TR criteria. Bivariate (Fisher exact test and Kruskal-Wallis rank sum test) and multivariate (logistic regression model fitting) analyses were performed.Results. Thirty-three (22%) subjects had post-surgical depressive episodes, 31 of them in the first 6 months. Fourteen out of 33 experienced depression for the first time. Post-surgical depressive episodes are not associated with gender, outcome on seizures, side/site of surgical resection, histological diagnosis, psychiatric diagnoses other than depression. Depressive episodes before surgery and older age at surgery time are risk factors for post-surgical depression (p = 0.0001 and 0.01, respectively, at logistic regression analysis). No protective factors were identified.Conclusions. Our data show that lifetime depressive episodes and older age at surgery time are risk factors for post-surgery depression. Moreover, a prospective study could be useful in order to assess whether depression is really a consequence of surgery.

Lurasidone is a novel second generation antipsychotic drug characterized by a multi-receptor profile. Besides the high affinity for 5-HT2A and D2 receptors, it is also characterized by potent 5-HT7 receptor antagonism, which may be beneficial for mood and cognition. Considering that dose-dependent changes in receptor occupancy may differentially impact gene transcription, we aimed at investigating the effects of acute and chronic treatments with different doses of lurasidone (1, 3 and 10 mg/kg) in rats on the expression of the activity-regulated genes Arc, Zif268 and Npas4, which are markers of neuronal activation and are also associated with neuroadaptive mechanisms. Our results show dose-dependent and anatomically-selective differences after acute and chronic lurasidone treatment. Indeed, the effects produced by acute treatment seem to reflect the modulatory activity of lurasidone at selected neurotransmitter receptors. In fact, low doses of the drug acted in the hippocampus, while high doses acted in the striatum, reflecting the high predominance of D2 receptor expression in this brain region. On the contrary, chronic treatment with lurasidone revealed a different profile of IEGs modulation, possibly reflecting neuroadaptive changes set in motion in response to repetitive drug exposure. In summary, the multi-receptor profile of lurasidone leads to the recruitment of different brain structures in a dose-related manner and this may be important for its therapeutic properties, particularly with respect to antidepressant activity and cognition.