Disrupted In Schizophrenia 1 Gene Research Articles

Transgenic Drosophila melanogaster Carrying a Human Full-Length DISC1 Construct (UAS-hflDISC1) Showing Effects on Social Interaction Networks.

Disrupted in Schizophrenia 1 (DISC1) is a scaffold protein implicated in major mental illnesses including schizophrenia, with a significant negative impact on social life. To investigate if DISC1 affects social interactions in Drosophila melanogaster, we created transgenic flies with second or third chromosome insertions of the human full-length DISC1 (hflDISC1) gene fused to a UAS promotor (UAS-hflDISC1). Initial characterization of the insertion lines showed unexpected endogenous expression of the DISC1 protein that led to various behavioral and neurochemical phenotypes. Social interaction network (SIN) analysis showed altered social dynamics and organizational structures. This was in agreement with the altered levels of the locomotor activity of individual flies monitored for 24 h. Together with a decreased ability to climb vertical surfaces, the observed phenotypes indicate altered motor functions that could be due to a change in the function of the motor neurons and/or central brain. The changes in social behavior and motor function suggest that the inserted hflDISC1 gene influences nervous system functioning that parallels symptoms of DISC1-related mental diseases in humans. Furthermore, neurochemical analyses of transgenic lines revealed increased levels of hydrogen peroxide and decreased levels of glutathione, indicating an impact of DISC1 on the dynamics of redox regulation, similar to that reported in transgenic mammals. Future studies are needed to address the localization of DISC1 expression and to address how the redox parameter changes correlate with the observed behavioral changes.

DISC1 as a prognostic biomarker correlated with immune infiltrates in gastric cancer

Multiple mental diseases could arise in people who have the disrupted in schizophrenia 1 (DISC1) gene. However, it was unknown how DISC1 might contribute to the development of tumors and immune responses. We extracted data from the Cancer Genome Atlas (TCGA) and TISIDB databases from stomach adenocarcinoma (STAD) patients, which revealed that DISC1 overexpression was closely associated with tumor histological type (mucinous vs. tubular, OR = 2.860, CI = 1.423–5.872, p = 0.004), as well as tumor stage and grade. Furthermore, the higher the DISC1 expression, the lower the overall 10-year survival rate. Patients with low DISC1 expression had a significantly longer progression-free interval (PFI) and disease-specific survival (DSS) than patients with high DISC1 expression. However, patients with higher DISC1 expression in the T3&T4, N0&N1 and M0 subgroups had poorer prognosis in terms of OS, DSS and PFI, as could be seen in the subgroup survival analysis. Public datasets were used to predict lncRNA-miRNA-DISC1 regulation. DISC1 was significantly up-regulated in GC(gastric cancer), and its expression levels showed a moderate to strong positive correlation with infiltration levels of effector memory T cells (Tem) and central memory T cells (Tcm), and a negative correlation was observed with Th17 cells and NK CD56bright cells. In addition, concomitant with the high expression of the DISC1 gene was a decrease in MHC-I (Major Histocompatibility Complex-I)expression and an increase in MHC-II expression, and altered chemokine expression. The upregulation of CXCL12 and CXCR4 expression could be caused by an increase in DISC1 expression.The above expression variability and correlation suggest a role for DISC1 in regulating tumor immunity in GC. These findings suggest that high expression of DISC1 could be an independent prognostic factor for GC.

Progression of behavioral deficits during periadolescent development differs in female and male DISC1 knockout rats.

Mutations in the disrupted in schizophrenia-1 (DISC1) gene are associated with an increased risk of developing psychological disorders including schizophrenia, bipolar disorder, and depression. Assessing the impact of knocking out genes, like DISC1, in animal models provides valuable insights into the relationship between the gene and behavioral outcomes. Previous research has relied on mouse models to assess these impacts, however these may not yield as reliable or rich a behavioral analysis as can be obtained using rats. Thus, the goal of the present study was to characterize the behavioral effects of a biallelic functional deletion of the DISC1 gene in the Sprague Dawley rat. Female and male wild type and DISC1 knockout rats were assessed beginning just prior to weaning and during the post-weaning periadolescent period. The primary outcomes evaluated were activity, anxiety, responses to novel objects and conspecifics, and prepulse inhibition. These behaviors were selected as analogous indices of psychological dysfunction in humans. The DISC1 knockout had significant effects on behavior, although the kind and magnitude of deficits was different for females and males: in females, effects included hyperactivity, aversion to novelty, and a modest prepulse inhibition deficit; in males, effects in anxiety and neophobia were mild but their prepulse inhibition deficit was large. These data confirm that the DISC1 knockout rat model is an excellent way to reproduce and study symptoms of psychological disorders and provides compelling evidence for differential consequences of its dysfunction for females and males in the progression and emergence of specific behavioral deficits.

Altered expression of the DISC1 gene in peripheral blood of patients with schizophrenia

BackgroundSchizophrenia is a severe, heritable, and refractory psychiatric disorder. Several studies have shown that the disrupted in schizophrenia 1 (DISC1) gene is closely associated with schizophrenia by its role in neuronal morphology, synaptic function, brain development, and dopamine homeostasis etc. This study intended to investigate the expression levels of DISC1 gene in schizophrenia patients compared with healthy controls, and the expression variation of DISC1 gene before and after antipsychotic treatment in schizophrenia patients.MethodsIn this study, we compared DISC1 expression levels in blood of 48 healthy controls, and 32 schizophrenia patients before and after 12 weeks of antipsychotic treatment using real-time quantitative PCR (RT-qPCR) analysis.ResultsThe expression levels of DISC1 gene in peripheral blood mononuclear cells of schizophrenia patients before antipsychotic treatment were higher than those in healthy controls (P < 0.01); whereas after antipsychotic treatment, the expression levels of DISC1 gene in peripheral blood mononuclear cells of schizophrenia patients still remained increased (P < 0.01).ConclusionsOur study provided further support for the involvement of DISC1 in the development of schizophrenia.

Anxiogenic-like behavior and deficient attention/working memory in rats expressing the human DISC1 gene

In humans, mutations in the Disrupted-in-schizophrenia 1 (DISC1) gene have been related to psychiatric disorders, including symptoms of abnormal cognitive and emotional behaviors. In our previous studies, overexpression of the human DISC1 gene in rats resulted in schizophrenia-like phenotypes showing deficits in motor learning, impaired cognitive function and dysfunctions of the dopamine system. Here we asked, whether the DISC1 overexpression affects locomotor activity in the open field (OF), anxiety in the elevated plus-maze (EPM), depression-related behavior in the forced swim test (FST), and attention-like/short-term working-memory in the spontaneous alternation behavior (SAB) in the T-maze in transgenic DISC1 (tgDISC1) rats and littermate controls (WT). TgDISC1 rats showed enhanced anxiety behavior in the EPM and an impairment in attention-like/short-term working-memory in the SAB. However, tgDISC1 animals showed no locomotor impairments or depression-like behavior in the OF and FST. These results suggest that DISC1 overexpression leads to higher anxiety level and an attention-like/working-memory deficit. These findings may expand the causal role of DISC1 in its contribution to multiple symptom dimensions of psychiatric disorders.

M101 - THE DISC1 GENE AND MAJOR MENTAL ILLNESS IN FINLAND

Background Linkage and association studies of major mental illness in Finland have continually identified the 1q42 region, and the Disrupted in Schizophrenia 1 (DISC1) gene in particular, as being a key locus of interest. Haplotypes and variants in the DISC1 gene have been associated with Schizophrenia (SCZ), bipolar disorder, and autism spectrum disorders, as well as to variations in related endophenotypes such as visual working memory, anhedonia, and gray matter volume in the dorsal lateral prefrontal cortex. Despite this consistent line of evidence for these loci in the Finnish population, any true causal variants within the DISC1 gene are yet to be identified. Methods To identify any potential mutations, a subset of families ascertained for SCZ (n=20 families, 96 individuals) were sequenced using Nimblegen SeqCap EZ for the DISC1 gene locus, including TSNAX. All identified variants were then prioritized using association analysis (p Results With the aid of this three-step sequencing and genotyping approach, we identified 1,828 variants in the DISC1 gene, of which 28 variants were identified as associated (p Discussion We aim to identify the potential mutations within the DISC1 gene which have been alluded to through our previous studies of Finnish cohorts for major mental illness. Our initial findings confirm the observation of association for several variants in the DISC1 gene for varied phenotypes, while focusing on the specific variants that have potential functional consequences. The variants we report may represent the principal major mental illness mutations within the DISC1 gene in the Finnish population. Once the relevance of these mutations to multiple diagnostic criteria is determined, we will study these mutations with respect to alternative phenotypes to the diagnoses available in these cohorts, including neuropsychological endophenotypes, neuroimaging, gene expression levels from lymphocytes, and medication usage.

SU104 - EXPERIMENTAL MODEL OF DISRUPTED IN SCHIZOPHRENIA 1 GENE IN A STEM CELL BASED NEURONAL MODEL

Background Induced Pluripotent Stem Cells (IPSCs) have the capability to differentiate into any kind of cell types, such as Neuronal Progenitor Cells (NPCs), and then to mature neurons. By this new approach we can investigate neuronal differentiation processes or the role of specific genes using genome editing techniques (e.g., ZFN, TALEN, or CRISPR). For example, the neuron-specific roles of the disrupted in schizophrenia 1 (DISC1) can be studied in a simple, Petri-dish based model. The DISC1gene has been intensively studied over the last decades after the description of a balanced translocation of t(1;11)(q42.1;q14.3) in a multigenerational Scottish family with several cases of psychosis and affective disorders, followed by the identification of a frameshift DISC1 mutation in an American family affected with schizophrenia. Previous molecular biological experiments have shown that DISC1 scaffold protein can affect neuronal proliferation and migration, and synapse maintenance. Animal model findings also pointed to its role in hippocampal neurogenesis, which is a crucial neuronal mechanism affected in several psychiatric disorders. Methods We aimed to characterize the possible roles of DISC1 in vitro neuronal cell culture. We applied an isogenic IPSC line in a model of hippocampal dentate gyrus neurogenesis, given that impaired hippocampal neurogenesis has been implicated in the pathogenesis of both schizophrenia and affective disorders. IPSC line XCL1 was engineered using zinc finger nuclease technology to produce an isogenic DISC1 exon-2 biallelic knockout cell line (XCL1 DISC1 exon-2 KO/KO). The locus of the genetic engineering was selected because of the frameshift mutation. The isogenic IPSC pair was characterized in terms of pluripotency and spontaneous differentiation potential. Following this, IPSC lines were differentiated into neuronal lineages using established protocols to generate hippocampal dentate gyrus granule cells. The dentate gyrus protocol is founded on dual SMAD inhibition, Wnt- and SHH inhibition, after generating free-floated embryoid bodies from pluripotent stem cells, which results in forebrain NPCs. Results We have successfully derived and characterized NPCs and then matured neurons from human IPSC XCL1 and deletion pair, which were differentiated according to the DG PROX1 protocol. There was no significant difference at the spontaneous differentiation potential between the isogenic IPSC XCL1 lines. The immunofluorescence staining showed that NPCs express Nestin and Sox2. This intermediate cell type can be further differentiated into PROX1 and MAP2 positive functional neurons which have dendritic spines. Till now we have not found significant differences between wild type and knock out cell lines based on induced outgrowth measurement and structure of ICC. We have found some alteration in Ca-dynamics between the two cell lines, however these measurements need further investigation. Discussion The generated neuronal progenitor cells and mature neurons carrying biallelic knockout of the DISC1 gene were amenable for assays comparing the isogenic pairs by immunofluorescence microscopy, and transcriptomics. Functional studies, such as calcium-imaging assays, single cell patch-clamp electrophysiology and real-time live cell visualization of induced neurite outgrowth are under way to further. These investigations may help to explore the role of DISC1 in hippocampal neurogenesis and the etiology of psychiatric disorders.

Emerging evidence for the role of pituitary adenylate cyclase-activating peptide in neuropsychiatric disorders.

Stress activates many brain nuclei and causes acute changes in several physiological and behavioral responses to restore homeostasis in affected organisms. While this response is protective, chronic stress exposure causes the sustained activation of these nuclei, leading to maladaptive physiological changes that underlie pathological mood and affective states. Hence, chronic stress may produce anxiety and mood disorders by promoting neuronal plasticity within these stress-responsive nuclei. A growing body of evidence attributes neuropeptide systems in mediating not only the physiological stress response but also pathological states that develop following chronic stress exposure. Recent preclinical data suggest that pituitary adenylyl cyclase-activating polypeptide (PACAP) and its receptors (PAC1, VPAC1, and VPAC2) play an important role in the behavioral and endocrine responses to stress, as well as in mood and affective disorders. Human studies also point out the significance of the PACAP/PAC1 receptor system in these disorders. For instance, PACAP through PAC1 receptor up-regulates the expression of DISC1 (disrupted in schizophrenia 1) and impedes its association with its interacting protein. Interestingly, the DISC1 gene mutation is linked to schizophrenia and depression. Moreover, a link between PACAP blood titer and fear physiology, post-traumatic stress disorder (PTSD) diagnosis and symptoms has been reported in heavily traumatized female patients. Additionally, in the peripheral blood, methylation of the gene encoding the PAC1 receptor is also associated with PTSD. This book chapter describes the emerging evidence that entails PACAP in the stress response and stress-mediated neuropsychiatric disorders.

Proteomic Studies Reveal Disrupted in Schizophrenia 1 as a Player in Both Neurodevelopment and Synaptic Function.

A balanced chromosomal translocation disrupting DISC1 (Disrupted in Schizophrenia 1) gene has been linked to psychiatric diseases, such as major depression, bipolar disorder and schizophrenia. Since the discovery of this translocation, many studies have focused on understating the role of the truncated isoform of DISC1, hypothesizing that the gain of function of this protein could be behind the neurobiology of mental conditions, but not so many studies have focused in the mechanisms impaired due to its loss of function. For that reason, we performed an analysis on the cellular proteome of primary neurons in which DISC1 was knocked down with the goal of identifying relevant pathways directly affected by DISC1 loss of function. Using an unbiased proteomic approach, we found that the expression of 31 proteins related to neurodevelopment (e.g., CRMP-2, stathmin) and synaptic function (e.g., MUNC-18, NCS-1) is altered by DISC1 in primary mouse neurons. Hence, this study reinforces the idea that DISC1 is a unifying regulator of both neurodevelopment and synaptic function, thereby providing a link between these two key anatomical and cellular circuitries.

DISC1 gene polymorphisms and the risk of schizophrenia in an Iranian population: A preliminary study.

Schizophrenia, schizoaffective disorder, and bipolar illness are common psychological disorders with high heritability and variable phenotypes. The disrupted in schizophrenia 1 ( DISC1) gene, on chromosome 1q42, has an essential role in neurite outgrowth and cell signaling. The purpose of this study was to investigate the association of three single-nucleotide polymorphisms (SNPs; rs6675281, rs2255340, and rs2738864) with schizophrenia disorder. These three SNPs were chosen as they had been used in most of the previous studies. In a case-control study of Iranian population for the first time 778 blood samples were collected including, 402 schizophrenic patients and 376 healthy controls. Genomic DNA was extracted from peripheral blood using DNA extraction kit (BioFlux Co). The genotypes of rs6675281, rs2255340, and rs2738864 were detected by nested allele-specific multiplex polymersae chain reaction (PCR). Our data revealed that the three SNPs are significantly associated with schizophrenia (rs2255349 C>T:confidence interval (CI), 2.115 to 3.268; P = 0.0000 OR: 2.629; rs2738864 C>T:CI, 1.538 to 2.339; P = 0.0000 OR: 1.897; rs6675281 C>T: CI, 2.788 to 4.662; P = 0.0009241 OR: 3.605). Through applying the expectation-maximization (EM) algorithm, we calculated the haplotype frequency, and finally performed haplotype analysis with Bonferroni correction and data preprocessing methods and the results showed rs66875281 to have the highest association. Our findings primarily showed that DISC1 gene polymorphisms contribute to schizophrenia risk and have a significant association with this disorder among Iranian population. The strategy was found to be easy, rapid, specific, and consistent for the co-occurring detection of the DISC1 polymorphisms. We could finally confirm that the polymorphisms are related to schizophrenia studied in Iranian population.

Association study of Disrupted-In-Schizophrenia-1 gene variants and tardive dyskinesia

Tardive dyskinesia (TD) is an involuntary movement disorder that occurs in ∼20% of patients after extended antipsychotic use. Its pathophysiology is unclear; however, familial patterns and gene association studies indicate an inherited component to risk. The disrupted in schizophrenia 1 (DISC1) gene was selected for analysis because it interacts with and regulates two important proteins involved in antipsychotic medication action: the dopamine D2 receptor and the cAMP phosphodiesterase type IVB (PDE4B). The D2 receptor is the obligate target of all existing antipsychotic medications, and PDE4B hydrolyzes cAMP, a core signaling molecule activated by agonist binding to the D2 receptor. Notably, PDE4B inhibitors such as rolipram have been shown to reduce TD-like behaviours in animal models. Nine single-nucleotide polymorphisms (SNPs) in the DISC1 gene were investigated in a sample of 193 chronic schizophrenia patients for association with the presence and severity of TD, with age and sex as additional variables. TD severity was measured using the Abnormal Involuntary Movement Scale (AIMS). Two DISC1 SNPs were associated with TD severity (uncorrected p < 0.05), but these findings did not survive correction for multiple testing. This preliminary investigation suggests that DISC1 gene variants do not affect risk for TD or severity.

Diminished Ca2+ Signaling, CaV1 Channel Expression, and Activity in Pancreatic Beta Cells Expressing Mutated DISC1 (Disrupted in Schizophrenia 1)

In addition to cognitive impairment, schizophrenics often suffer from non-obese T2D. Here, we examined whether similar cellular changes occur in pancreatic beta-cells as found in neurons from a genetic model of schizophrenia. Specifically we tested whether beta-cells exhibit disrupted excitation-secretion coupling when a truncated human DISC1 (thDISC1) gene, originally discovered in a Scottish family having high penetrance for schizophrenia, is expressed selectively in mouse beta-cells upon ingesting doxycycline (+DOX). Expression of thDISC1 significantly decreases blood insulin levels and GSIS from isolated mouse islets, revealing an independent role for DISC1 in beta-cells. In central neurons, DISC1 regulates Ca2+ CaV2 channel expression, Ca2+ influx and transmitter release. To determine whether DISC1 similarly regulates Ca2+ physiology in beta-cells, we tested thDISC1 DOX+ vs. DOX- beta-cells for changes in: i) intracellular Ca2+signaling using Fluo 3-AM; ii) CaV1 channel expression, the dominant channel class controlling GSIS; iii) and CaV1 channel activity using whole-cell recording methods. We found increases in [Ca2+]i following 20 mM glucose were delayed &amp;gt;2 min and diminished ∼50% in dissociated beta-cells expressing thDISC1. When sections of pancreas were stained with an anti-CaV1.2/1.3 antibody, thDISC1 DOX+ vs. DOX- insulin-positive cells exhibited decreased staining. Lastly, both peak inward Ba2+ current and FPL 64176 induced long-lasting L-type tail current decreased significantly in thDISC1 DOX+ vs. DOX- beta-cells. No obvious change in activation kinetics was observed. These changes in excitation-secretion coupling parallel those in neurons expressing truncated DISC1. Thus at the cellular level, truncated DISC1 precipitates disorders of secretion such as schizophrenia and T2D. Disclosure P. Lu: None. R.B. Sharma: None. L.C. Alonso: None. R. Zhuge: None. A.R. Rittenhouse: None. A. Jurczyk: None.

English

Schizophrenia is a common health problem in the world, including in Indonesia. Polymorphism of gene disrupted in schizophrenia 1 (DISC1) Leu607Phe is allegedly related to the predisposition to schizophrenia. However, studies on the relationship between polymorphism of DISC1 Leu607Phe and schizophrenia in various etnics provided different results. The purpose of this study was to determine the frequency of DISC1 Leu607Phegene polymorphism and its association with treatment response in patients with schizophrenia at Department of Psychiatry, Dr. Soetomo General Hospital Surabaya. In this study, the number of male patients with schizophrenia was more than that of the female patients. The mean age of male patients with schizophenia was lower than that of the female patients. Schizophrenia patients were primarily came from Javanese ethnic with positive and negative symptom score (PANSS) lower in male patients than that in the female patients. In conclusion, no DISC1 gene polymorphism at codon 607 is observed in schizophrenia patients at Dr. Soetomo General Hospital Surabaya, but the G nucleotide variation at the number 196.339 in intron regions is found instead.

Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene

The Disrupted-in-Schizophrenia 1 (DISC1) gene has been associated with mental illnesses such as major depression and schizophrenia. The transgenic DISC1 (tgDISC1) rat, which overexpresses the human DISC1 gene, is known to exhibit deficient dopamine (DA) homeostasis. To ascertain whether the DISC1 gene also impacts cognitive functions, 14–15 months old male tgDISC1 rats and wild-type controls were subjected to the novel object preference (NOP) test and the object-based attention test (OBAT) in order to assess short-term memory (1 h), long-term memory (24 h), and attention. Results: The tgDISC1 group exhibited intact short-term memory, but deficient long-term-memory in the NOP test and deficient attention-related behavior in the OBAT. In a different group of tgDISC1 rats, 3 mg/kg intranasally applied dopamine (IN-DA) or its vehicle was applied prior to the NOP or the OBAT test. IN-DA reversed cognitive deficits in both the NOP and OBAT tests. In a further cohort of tgDISC1 rats, post-mortem levels of DA, noradrenaline, serotonin and acetylcholine were determined in a variety of brain regions. The tgDISC1 group had less DA in the neostriatum, hippocampus and amygdala, less acetylcholine in neostriatum, nucleus accumbens, hippocampus, and amygdala, more serotonin in the nucleus accumbens, and less serotonin and noradrenaline in the amygdala. Conclusions: Our findings show that DISC1 overexpression and misassembly is associated with deficits in long-term memory and attention-related behavior. Since behavioral impairments in tgDISC1 rats were reversed by IN-DA, DA deficiency may be a major cause for the behavioral deficits expressed in this model.

M57 - DISC1 Gene Network Mutations In Major Mental Illness

Background The genetic etiology of schizophrenia (SCZ) has been studied in a familial Finnish cohort since the late 1980s. Over the years, linkage and association studies of these families have continually identified the 1q42 region, and the Disrupted in Schizophrenia 1 (DISC1) gene in particular, as being a key locus of interest. Haplotypes and variants in the DISC1 gene have also been noted to associate with the risk to other mental illnesses in the Finnish population, including bipolar disorder and autism spectrum disorders, as well as to variations in phenotypes such as visual working memory, anhedonia, and gray matter volume in the dorsal lateral prefrontal cortex. Furthermore, studies in the SCZ family cohort have also observed association at genes for DISC1 interacting partners, the DISC1 network, including NDE1, PDE4D, PDE4B, and NDEL1. Despite this consistent line of evidence for these loci in the Finnish population, any true causal variants have yet to be identified. Methods To identify any potential mutations a subset of SCZ families (n=20 families, 96 individuals) were sequenced at 24 genes from the extended DISC1 network. All identified variants were then prioritized using association analysis (p Results With the aid of the three step sequencing and genotyping approach, we identified 12,795 variants in the DISC1 gene network, of which 67 variants from 9 genes were identified as associated (p Discussion This research aims to identify the potential mutations within the DISC1 network which have been alluded to through our previous studies of Finnish cohorts for major mental illness. Our initial findings confirm the observation of association at a number of DISC1 network genes, including DISC1 itself, while focusing on the specific variants at these loci that have potential functional consequences. Thus, the variants we are observing may represent the principal mutations at these loci in the Finnish population, and predispose to psychiatric disorders beyond schizophrenia.

Expression Alteration of Disrupted in Schizophrenia 1 (DISC1) Gene, a Potential Peripheral Marker for Schizophrenia and Paranoid Personality Disorder

Introduction: Schizophrenia (SCZ) is a major psychiatric disorder with unclear etiology or biological diagnosis. Paranoid Personality Disorder (PPD) is a type A personality disorder characterized by paranoia and generalized mistrust. Disrupted in schizophrenia 1 (DISC1) is a gene located on human chromosome 1 that is involved in neurodevelopment of brain. Variations and translocations in this gene were found associated with schizophrenia and other psychiatric disorders. Present study aimed to evaluate the expression alteration of DISC1 gene in peripheral blood of SCZ and PPD patients and its correlation with clinical features. Material and methods: Study was included 300 SCZ, 300 PPD and 300 non-psychiatric individuals. Total blood was collected and expression level of DISC1 evaluated by using quantitative Real time PCR SYBR green. Lymphocyte DISC1 protein levels in all subjects were examined. Also, to assess psychiatric symptoms severity, Positive and Negative Syndrome Scale (PANSS) was obtained from SCZ and PPD patients. For analysis of executive functions abilities, Wisconsin Card Sorting Test (WCST) had been conducted from all subjects. Results: Findings showed significant DISC1 gene down expression in SCZ and PPD patients vs. non-psychiatrics. DISC1 protein levels were significantly decreased in SCZ and PPD vs. non-psychiatrics. Also in SCZ patients, general and negative symptoms score were associated with down regulation of DISC1 mRNA level. Executive functions deficiency had detected in SCZ and PPD and correlations were found between decrease in WSCT correct response and down expression of DISC1 in SCZ and PPD patients. Discussion and conclusion: Results presented DISC1 as potential peripheral marker for schizophrenia as well as paranoid personality disorder. Correlation between DISC1 mRNA level reduction and severity of general and negative symptoms in one side and executive functions abnormalities in the other side may support the neurodevelopment hypothesis about pathophysiology of schizophrenia and related personality disorder especially paranoid personality disorder.

Altered cytokine profile, pain sensitivity, and stress responsivity in mice with co-disruption of the developmental genes Neuregulin-1 × DISC1

The complex genetic origins of many human disorders suggest that epistatic (gene×gene) interactions may contribute to a significant proportion of their heritability estimates and phenotypic heterogeneity. Simultaneous disruption of the developmental genes and schizophrenia risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) in mice has been shown to produce disease-relevant and domain-specific phenotypic profiles different from that observed following disruption of either gene alone. In the current study, anxiety and stress responsivity phenotypes in male and female mutant mice with simultaneous disruption of DISC1 and NRG1 were examined. NRG1×DISC1 mutant mice were generated and adult mice from each genotype were assessed for pain sensitivity (hot plate and tail flick tests), anxiety (light-dark box), and stress-induced hypothermia. Serum samples were assayed to measure circulating levels of pro-inflammatory cytokines. Mice with the NRG1 mutation, irrespective of DISC1 mutation, spent significantly more time in the light chamber, displayed increased core body temperature following acute stress, and decreased pain sensitivity. Basal serum levels of cytokines IL8, IL1β and IL10 were decreased in NRG1 mutants. Mutation of DISC1, in the absence of epistatic interaction with NRG1, was associated with increased serum levels of IL1β. Epistatic effects were evident for IL6, IL12 and TNFα. NRG1 mutation alters stress and pain responsivity, anxiety, and is associated with changes in basal cytokine levels. Epistasis resulting from synergistic NRG1 and DISC1 gene mutations altered pro-inflammatory cytokine levels relative to the effects of each of these genes individually, highlighting the importance of epistatic mechanisms in immune-related pathology.

Stimulation of Synaptic Vesicle Exocytosis by the Mental Disease Gene DISC1 is Mediated by N-Type Voltage-Gated Calcium Channels.

Lesions and mutations of the DISC1 (Disrupted-in-schizophrenia-1) gene have been linked to major depression, schizophrenia, bipolar disorder and autism, but the influence of DISC1 on synaptic transmission remains poorly understood. Using two independent genetic approaches—RNAi and a DISC1 KO mouse—we examined the impact of DISC1 on the synaptic vesicle (SV) cycle by population imaging of the synaptic tracer vGpH in hippocampal neurons. DISC1 loss-of-function resulted in a marked decrease in SV exocytic rates during neuronal stimulation and was associated with reduced Ca2+ transients at nerve terminals. Impaired SV release was efficiently rescued by elevation of extracellular Ca2+, hinting at a link between DISC1 and voltage-gated Ca2+ channels. Accordingly, blockade of N-type Cav2.2 channels mimics and occludes the effect of DISC1 inactivation on SV exocytosis, and overexpression of DISC1 in a heterologous system increases Cav2.2 currents. Collectively, these results show that DISC1-dependent enhancement of SV exocytosis is mediated by Cav2.2 and point to aberrant glutamate release as a probable endophenotype of major psychiatric disorders.

Erratum to: Polymorphism of rs3737597 in DISC1 Gene on Chromosome 1q42.2 in sALS Patients: a Chinese Han Population Case-Control Study.

Although lots of genes have been revealed to relate to sporadic amyotrophic lateral sclerosis (sALS), its genetic mechanisms still need to be further explored. We aimed to search the novel genetic factors of sALS and assess their contribution. We constructed an integrative dataset based on the 3227 subsignificant genes (P value < 0.01) from two sALS-related genome-wide association studies (GWAS) (the US and Irish studies). A significant replication between both studies was confirmed by the gene set enrichment analysis in the integral level (P value < 10−4). Using the pathway overrepresentation analysis, we revealed the 34 shared Gene Ontology (GO) biological processes from the two independent studies (P value < 0.01). Among these pathways, the nervous system developmental pathway (NSD function, GO:0007399) was further supported by the previously reported genes related to sALS (P value = 3.28e−12). Importantly, four of 17 NSD-function-related target genes (disrupted-in-schizophrenia-1 (DISC1), CNTN4, NRXN3, and ERBB4) presented a considerable association with sALS in both studies. To further verify the association between the NSD function target genes and sALS, we preformed a two-stage case–control study based on 500 sALS patients and 500 controls of Chinese Han populations from mainland. A polymorphism of rs3737597 in DISC1 gene involved in the nervous system developmental pathway was closely associated with sALS. The nervous system developmental pathway is a potential pathogenesis of sALS, among them, the polymorphism of rs3737597 in DISC1 might play some roles.

Polymorphism of rs3737597 in DISC1 Gene on Chromosome 1q42.2 in sALS Patients: a Chinese Han Population Case-Control Study.

Although lots of genes have been revealed to relate to sporadic amyotrophic lateral sclerosis (sALS), its genetic mechanisms still need to be further explored. We aimed to search the novel genetic factors of sALS and assess their contribution. We constructed an integrative dataset based on the 3227 subsignificant genes (P value < 0.01) from two sALS-related genome-wide association studies (GWAS) (the US and Irish studies). A significant replication between both studies was confirmed by the gene set enrichment analysis in the integral level (P value < 10-4). Using the pathway overrepresentation analysis, we revealed the 34 shared Gene Ontology (GO) biological processes from the two independent studies (P value < 0.01). Among these pathways, the nervous system developmental pathway (NSD function, GO:0007399) was further supported by the previously reported genes related to sALS (P value = 3.28e-12). Importantly, four of 17 NSD-function-related target genes (disrupted-in-schizophrenia-1 (DISC1), CNTN4, NRXN3, and ERBB4) presented a considerable association with sALS in both studies. To further verify the association between the NSD function target genes and sALS, we preformed a two-stage case-control study based on 500 sALS patients and 500 controls of Chinese Han populations from mainland. A polymorphism of rs3737597 in DISC1 gene involved in the nervous system developmental pathway was closely associated with sALS. The nervous system developmental pathway is a potential pathogenesis of sALS, among them, the polymorphism of rs3737597 in DISC1 might play some roles.