Dysbindin Gene Research Articles

Loss of dysbindin-1 in excitatory neurons in mice impacts NMDAR-dependent behaviors, neuronal morphology and synaptic transmission in the ventral hippocampus

Dysbindin-1, a protein encoded by the schizophrenia susceptibility gene DTNBP1, is reduced in the hippocampus of schizophrenia patients. It is expressed in various cellular populations of the brain and implicated in dopaminergic and glutamatergic transmission. To investigate the impact of reduced dysbindin-1 in excitatory cells on hippocampal-associated behaviors and synaptic transmission, we developed a conditional knockout mouse model with deletion of dysbindin-1 gene in CaMKIIα expressing cells. We found that dysbindin-1 reduction in CaMKII expressing cells resulted in impaired spatial and social memories, and attenuation of the effects of glutamate N-methyl-d-asparate receptor (NMDAR) antagonist MK801 on locomotor activity and prepulse inhibition of startle (PPI). Dysbindin-1 deficiency in CaMKII expressing cells also resulted in reduced protein levels of NMDAR subunit GluN1 and GluN2B. These changes were associated with increased expression of immature dendritic spines in basiliar dendrites and abnormalities in excitatory synaptic transmission in the ventral hippocampus. These results highlight the functional relevance of dysbindin-1 in excitatory cells and its implication in schizophrenia-related pathologies.

Schizophrenia-related dysbindin-1 gene is required for innate immune response and homeostasis in the developing subventricular zone

Schizophrenia is a neurodevelopmental disorder likely caused by environmental and genetic risk factors but functional interactions between the risk factors are unclear. We tested the hypothesis that dysbindin-1 (Dtnbp1) gene mutation combined with postnatal exposure to viral mimetic polyI:C results in schizophrenia-related behavioural changes in adulthood, and mediates polyI:C-induced inflammation in the subventricular zone (SVZ). Adult Sandy (Sdy, Dtnbp1 mutant) mice given early postnatal polyI:C injections displayed reduced prepulse inhibition of startle, reduced locomotion and deficits in novel object recognition. PolyI:C induced a canonical immune response in the SVZ; it increased mRNA expression of its toll-like receptor 3 (Tlr3) and downstream transcription factors RelA and Sp1. PolyI:C also increased SVZ Dtnbp1 mRNA expression, suggesting dysbindin-1 regulates immune responses. Dysbindin-1 loss in Sdy mice blocked the polyI:C-induced increases in mRNA expression of Tlr3, RelA and Sp1 in the SVZ. Dtnbp1 overexpression in SVZ-derived Sdy neurospheres rescued Tlr3, RelA and Sp1 mRNA expression supporting a functional interaction between dysbindin-1 and polyI:C-induced inflammation. Immunohistochemistry showed higher Iba1+ immune cell density in the SVZ of Sdy mice than in WT postnatally. PolyI:C did not alter SVZ Iba1+ cell density but increased CD45+/Iba1− cell numbers in the SVZ of Sdy mice. Finally, polyI:C injections in Sdy, but not WT mice reduced postnatal and adult SVZ proliferation. Together, we show novel functional interactions between the schizophrenia-relevant dysbindin-1 gene and the immune response to polyI:C. This work sheds light on the molecular basis for amplified abnormalities due to combined genetic predisposition and exposure to environmental schizophrenia risk factors.

S185. DTNBP1 IS ASSOCIATED WITH THE AGE AT ONSET OF KOREAN PATIENTS WITH SCHIZOPHRENIA

BackgroundThe dysbindin gene (DTNBP1) is located in chromosome 6p22.3, one of the regions of positive linkage for schizophrenia. In particular, dysbindin protein has been found to play a role in the glutatmate neural transmission in the brain. A strong genetic association between DTNBP1 and schizophrenia has been replicated through many recent studies. However, we have not replicated positive association between DTNBP1 and schizophrenia in our Korean sample. Because schizophrenia has been regarded as a disease with a quite heterogeneous origin and evolvement, it is useful to categorize patients with schizophrenia into relatively homogeneous subsets based on clinical characteristics including age at onset (AAO). We investigated the association between DTNBP1 and AAO of schizophrenia.MethodsWe assessed age at first occurrence of positive psychotic symptoms of 197 patients with schizophrenia with DSM IV diagnosis, which was re-evaluated by Korean version of Diagnostic Interview for Genetic Study. Five SNPs, SNPA, P1763, P1320, P1635 and P1655 of DTNBP1 were genotyped and genetic association analyses were performed using the PLINK program.ResultsIn SNPA, patients with AT (N=10) showed significant earlier AAO than those with AA (N=187) (p<0.0001). The patients with heterozygote for SNP P1763 (TG, N=40) or P1320 (CT, N=41) also showed significant earlier AAO than those with homozygote (P<0.0001, P<0.0001, respectively). In addition, haplotype of all SNPs (SNPA-P1320-P1635-P1655-P1763) analysis showed significant association with AAO (p=0.000953).DiscussionIn conclusion, although we were unable to support an association between DTNBP1 and schizophrenia, DTNBP1 might play a role in disease modifying. However, considering the several limitations of this study, further research involving different polymorphisms in DTNBP1 and various clinical subsets with sufficient numbers will be required to evaluate the contribution of DTNBP1 to schizophrenia.

Dysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles

Here we explore the relationship between presynaptic homeostatic plasticity and proteasome function at the Drosophila neuromuscular junction. First, we demonstrate that the induction of homeostatic plasticity is blocked after presynaptic proteasome perturbation. Proteasome inhibition potentiates release under baseline conditions but not during homeostatic plasticity, suggesting that proteasomal degradation and homeostatic plasticity modulate a common pool of vesicles. The vesicles that are regulated by proteasome function and recruited during homeostatic plasticity are highly EGTA sensitive, implying looser Ca2+ influx-release coupling. Similar to homeostatic plasticity, proteasome perturbation enhances presynaptic Ca2+ influx, readily-releasable vesicle pool size, and does not potentiate release after loss of specific homeostatic plasticity genes, including the schizophrenia-susceptibility gene dysbindin. Finally, we provide genetic evidence that Dysbindin levels regulate the access to EGTA-sensitive vesicles. Together, our data suggest that presynaptic protein degradation opposes the release of low-release probability vesicles that are potentiated during homeostatic plasticity and whose access is controlled by dysbindin.

Increased dysbindin-1B isoform expression in schizophrenia and its propensity in aggresome formation.

Genetic variations in the human dysbindin-1 gene (DTNBP1) have been associated with schizophrenia. As a result of alternative splicing, the human DTNBP1 gene generates at least three distinct protein isoforms, dysbindin-1A, -1B and -1C. Significant effort has focused on dysbindin-1A, an important player in multiple steps of neurodevelopment. However, the other isoforms, dysbindin-1B and dysbindin-1C have not been well characterized. Nor have been associated with human diseases. Here we report an increase in expression of DTNBP1b mRNA in patients with paranoid schizophrenia as compared with healthy controls. A single-nucleotide polymorphism located in intron 9, rs117610176, has been identified and associated with paranoid schizophrenia, and its C allele leads to an increase of DTNBP1b mRNA splicing. Our data show that different dysbindin splicing isoforms exhibit distinct subcellular distribution, suggesting their distinct functional activities. Dysbindin-1B forms aggresomes at the perinuclear region, whereas dysbindin-1A and -1C proteins exhibit diffused patterns in the cytoplasm. Dysbindin-1A interacts with dysbindin-1B, getting recruited to the aggresome structure when co-expressed with dysbindin-1B. Moreover, cortical neurons over-expressing dysbindin-1B show reduction in neurite outgrowth, suggesting that dysbindin-1B may interfere with dysbindin-1A function in a dominant-negative manner. Taken together, our study uncovers a previously unknown association of DTNBP1b expression with schizophrenia in addition to its distinct biochemical and functional properties.

Recognition deficits in mice carrying mutations of genes encoding BLOC-1 subunits pallidin or dysbindin.

Numerous studies have implicated DTNBP1, the gene encoding dystrobrevin-binding protein or dysbindin, as a candidate risk gene for schizophrenia, though this relationship remains somewhat controversial. Variation in dysbindin, and its location on chromosome 6p, has been associated with cognitive processes, including those relying on a complex system of glutamatergic and dopaminergic interactions. Dysbindin is one of the seven protein subunits that comprise the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin protein levels are lower in mice with null mutations in pallidin, another gene in the BLOC-1, and pallidin levels are lower in mice with null mutations in the dysbindin gene, suggesting that multiple subunit proteins must be present to form a functional oligomeric complex. Furthermore, pallidin and dysbindin have similar distribution patterns in a mouse and human brain. Here, we investigated whether the apparent correspondence of pallid and dysbindin at the level of gene expression is also found at the level of behavior. Hypothesizing a mutation leading to underexpression of either of these proteins should show similar phenotypic effects, we studied recognition memory in both strains using the novel object recognition task (NORT) and social novelty recognition task (SNRT). We found that mice with a null mutation in either gene are impaired on SNRT and NORT when compared with wild-type controls. These results support the conclusion that deficits consistent with recognition memory impairment, a cognitive function that is impaired in schizophrenia, result from either pallidin or dysbindin mutations, possibly through degradation of BLOC-1 expression and/or function.

Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice.

The expression of dysbindin-1, a protein coded by the risk gene dtnbp1, is reduced in the brains of schizophrenia patients. Evidence indicates a role of dysbindin-1 in dopaminergic and glutamatergic transmission. Glutamatergic transmission and plasticity at excitatory synapses is critically regulated by G-protein coupled metabotropic glutamate receptor (mGluR) family members, that have been implicated in schizophrenia. Here, we report a role of dysbindin-1 in hippocampal group 1 mGluR (mGluRI) function in mice. In hippocampal synaptoneurosomal preparations from sandy (sdy) mice, that have a loss of function mutation in dysbindin-1 gene, we observed a striking reduction in mGluRI agonist [(S)-3, 5-dihydroxyphenylglycine] (DHPG)-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2). This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5) or in another mGluRI signaling pathway, i.e., protein kinase C (PKC). Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD) at CA1 excitatory synapses was significantly reduced. Behavioral data suggest that the mGluRI hypofunction may underlie some of the cognitive abnormalities described in sdy mice as the administration of CDPPB (3-cyano-N-(1, 3-diphenyl-1H-pyrazol-5-yl benzamide), a positive allosteric modulator of mGluR5, rescued short-term object recognition and spatial learning and memory deficits in these mice. Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

Dysbindin gene variability is associated with cognitive abnormalities in first-episode non-affective psychosis

Introduction. Dystrobrevin-binding protein 1 gene (dysbindin or DTNBP1) has been associated with schizophrenia and cognitive performance. Its expression in areas implicated in cognition such as the dorsolateral prefrontal cortex, as well as its role in dopaminergic and glutamatergic system, has been replicated by several studies. The main aim of this study was to examine the association between DTNBP1 variability and cognitive performance in a sample of 238 patients with a first episode of a non-affective psychosis.Methods. Patients, and a comparison sample of 47 healthy subjects, completed an extensive neuropsychological battery. Five single nucleotide polymorphisms (SNPs) within DTNBP1 (rs2619528, rs2619538, rs3213207, rs2619539 and rs760761) and three haplotypes (GACAC, GAGAC and GTGAC) were analysed.Results. In the group of patients, we found a significant association between two of the DTNBP1 SNPs and one of the haplotypes (rs2619539, rs3213207 and GACAC) and a measure of premorbid IQ [Wechsler Adult Intelligence Scale-3rd Edition (WAIS-III) Vocabulary subtest]. Moreover, one of these SNPs, rs2619539, was also associated with our measure of working memory (WAIS-III Backward digits subtest) and two haplotypes, GAGAC and GTGAC, with our measure of verbal memory (Rey Auditory Verbal Learning Test), of visual memory (Rey Complex Figure Test) in the case of GAGAC, and of speed of processing (WAIS-III Digit Symbol-coding) in the case of GTGAC.Conclusions. Our findings add further evidence suggesting an association between dysbindin gene variability and cognitive abnormalities in schizophrenia, providing preliminary evidence of this association since the time of illness onset among minimally medicated patients.

Behavioral characterization of mice overexpressing human dysbindin-1.

BackgroundThe dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous Dtnbp1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if dysbindin-1 gain-of-function is beneficial or detrimental.ResultsTo answer this question and gain further insight into the pathophysiology and therapeutic potential of dysbindin-1, we developed transgenic mice expressing human DTNBP1 (Dys1A-Tg) and analyzed their behavioral phenotypes. Dys1A-Tg mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function showed a marginal change in limb grasping in Dys1A-Tg mice. In addition, Dys1A-Tg mice exhibited increased hyperlocomotion after methamphetamine injection. Transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes Arc and Egr2, in the prefrontal cortex of Dys1A-Tg mice.ConclusionsThe present findings in Dys1A-Tg mice support the role of dysbindin-1 in psychiatric disorders. The fact that either overexpression (Dys1A-Tg) or underexpression (Sandy) of dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of dysbindin-1 in vivo.

Mutations in the BLOC-1 Subunits Dysbindin and Muted Generate Divergent and Dosage-dependent Phenotypes

Post-mortem analysis has revealed reduced levels of the protein dysbindin in the brains of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss of function mutations in the genes encoding dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5(mu/mu)) and dysbindin (Bloc1s8(sdy/sdy)). Transcripts of NMDA receptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5(mu/mu) and Bloc1s8(sdy/sdy) mice. Unlike Bloc1s8(sdy/sdy), elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders.

The β-alanyl-monoamine synthase ebony is regulated by schizophrenia susceptibility gene dysbindin in Drosophila

The Drosophila homolog of schizophrenia susceptibility gene dysbindin (Ddysb) affects a range of behaviors through regulation of multiple neurotransmitter signals, including dopamine activity. To gain insights into mechanisms underlying Ddysb-dependent regulation of dopamine signal, we investigated interaction between Ddysb and Ebony, the Drosophila β-alanyl-monoamine synthase involved in dopamine recycling. We found that Ddysb was capable of regulating expression of Ebony in a bi-directional manner and its subcellular distribution. Such regulation is confined to glial cells. The expression level of ebony and its accumulation in glial soma depend positively on Ddysb activity, whereas its distribution in glial processes is bound to be reduced in response to any alterations of Ddysb from the normal control level, either an increase or decrease. An optimal binding ratio between Dysb and Ebony might contribute to such non-linear effects. Thus, Ddysb-dependent regulation of Ebony could be one of the mechanisms that mediate dopamine signal.

Age-dependent regulation of synaptic connections by dopamine D2 receptors.

Dopamine D2 receptors (D2R) are G protein–coupled receptors that modulate synaptic transmission and play an important role in various brain functions including affect learning and working memory. Abnormal D2R signaling has been implicated in psychiatric disorders such as schizophrenia. Here we report a new function of D2R in dendritic spine morphogenesis. Activation of D2R reduces spine number via GluN2B– and cAMP–dependent mechanisms in mice. Notably, this regulation takes place only during adolescence. During this period, D2R overactivation caused by mutations in the schizophrenia–risk–gene dysbindin leads to spine deficiency, dysconnectivity within the entorhinal–hippocampal circuit and impairment of spatial working memory. Notably, these defects can be ameliorated by D2R blockers administered during adolescence. These findings uncover a novel age–dependent function of D2R in spine development, provide evidence that D2R dysfunction during adolescence impairs neuronal circuits and working memory, and suggest that adolescent interventions of aberrant D2R activity protect against cognitive impairment.

P.1.a.012 Association between dysbindin gene and cerebral structures in a Spanish population

Dystrobrevin binding protein 1 (DTNBP1), or dysbindin, is thought to be critical in regulating the glutamatergic system. While the dopamine pathway is known to be important in the aetiology of schizophrenia, it seems likely that glutamatergic dysfunction can lead to the development of schizophrenia. DTNBP1 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and a DTNBP1 polymorphism has been associated with reduced brain expression. Despite numerous genetic studies no DTNBP1 polymorphism has been strongly implicated in schizophrenia aetiology. Using a haplotype block-based gene-tagging approach we genotyped 13 SNPs in DTNBP1 to investigate possible associations with DTNBP1 and schizophrenia. Four polymorphisms were found to be significantly associated with schizophrenia. The strongest association was found with an A/C SNP in intron 7 (rs9370822). Homozygotes for the C allele of rs9370822 were more than two and a half times as likely to have schizophrenia compared to controls. The other polymorphisms showed much weaker association and are less likely to be biologically significant. These results suggest that DTNBP1 is a good candidate for schizophrenia risk and rs9370822 is either functionally important or in disequilibrium with a functional SNP, although our observations should be viewed with caution until they are independently replicated.

Developmental expression of dysbindin in Muller cells of rat retina

Dysbindin, the product of the DTNBP1 gene, was identified by yeast two hybrid assay as a binding partner of dystrobrevin, a cytosolic component of the dystrophin protein complex. Although its functional role has not yet been completely elucidated, the finding that dysbindin assembles into the biogenesis of lysosome related organelles complex 1 (BLOC-1) suggests that it participates in intracellular trafficking and biogenesis of organelles and vesicles. Dysbindin is ubiquitous and in brain is expressed primarily in neurons. Variations at the dysbindin gene have been associated with increased risk for schizophrenia. As anomalies in retinal function have been reported in patients suffering from neuropsychiatric disorders, we investigated the expression of dysbindin in the retina. Our results show that differentially regulated dysbindin isoforms are expressed in rat retina during postnatal maturation. Interestingly, we found that dysbindin is mainly localized in Müller cells. The identification of dysbindin in glial cells may open new perspectives for a better understanding of the functional involvement of this protein in visual alterations associated to neuropsychiatric disorders.

Abnormalities in extracellular glycine and glutamate levels in the striatum of sandy mice.

Glycine regulates glutamatergic neurotransmission, and several papers have reported the relationship between glycine and schizophrenia. The dysbindin-1 (DTNBP1: dystrobrevin-binding protein 1) gene is related to glutamatergic neurotransmission and has been found to be a strong candidate gene for schizophrenia. In this study, we clarified the relationship between dysbindin, glutamate, and glycine with in vivo microdialysis methods. We measured extracellular glycine and glutamate levels in the striatum of sandy (sdy) mice using in vivo microdialysis methods. Sdy mice express no dysbindin protein owing to a deletion in the dysbindin-1 gene. In addition, we measured changes in those amino acids after methamphetamine (METH) administration. The basal levels of extracellular glycine and glutamate in the striatum of sdy mice were elevated. These extracellular glutamate levels decreased gradually after METH administration and were not subsequently different from those of wild-type mice. These results suggest that dysbindin might modulate glycine and glutamate release in vivo.

Schizophrenia: brain morphology and treatment aspects

Since the first findings of enlarged ventricles in computer tomography studies and with the development of MRIbased segmentation, brain morphology findings in schizophrenia point to abnormal structural findings in several brain regions involved in neuronal circuits [1]. One of the often cited environmental risk factors in schizophrenia is cannabis abuse. In an invited review, Malchow et al. [2], however, found inconclusive results with respect to alterations in brain morphology. They assume that chronic cannabis abuse may induce structural changes, whereas in first-episode and high-risk patients, studies need replication. In subjects at high risk and patients with schizophrenia, the gyrification index as a measure of cortico-cortical connection differed from healthy controls in the frontal and parietal cortex [3]. This may be based on the neurodevelopmental abnormalities, since the gyrification pattern is determined during the perinatal period. Accordingly, in a recent postmortem study, a reduced gyrification index has been observed in the parietal cortex in schizophrenia [4] showing no differences between monozygotic twins compared to dizygotic twin pairs which points to the influence of different intrauterine and postnatal factors [5]. Postmortem studies with a resolution on the cellular and even molecular level with, for example, focus on synaptic structural elements [6] may contribute to elucidate the pathophysiology of schizophrenia. Williams et al. [7] investigated neuronal cell density and found decreased pyramidal layer thickness resulting in decreased frontal lobe thickness in schizophrenia patients. They additionally report decreased astrocyte density in the subgenual cingulated cortex and callosal genu for their sample [8], which extends neurobiological hypotheses on the dysfunction of astrocytes in maintaining synaptic stability. Investigations in healthy subjects are indispensable to elucidate risk factors influencing brain volumes and for exclusion of confounding factors such as other diseaserelated and treatment effects. Beside environmental factors, schizophrenia risk genes may contribute to altered brain structures. Trost et al. [9] found a dysbindin-1 gene variant to be associated with hippocampal and prefrontal gray matter volumes. On the molecular level, another risk gene such as brain-derived neurotrophic factor (BDNF) val66met polymorphism has been shown to affect the glutamate system [10]. Moreover, D-amino acid oxidase activator gene (DAOA) variation has been found to affect homovanillic acid levels in cerebrospinal fluid [11]. Unraveling neurobiological effects of such risk factors may contribute to develop a more personalized medicine in psychiatry [12]. Even effects of traditional neuroleptic treatment strategies may be influenced by genetic factors. Giegling et al. [13] found that three haplotype blocks, one among ankyrin repeat and kinase domain containing 1 (ANKK1) and two among dopamine receptor D2 (DRD2) genes, were associated with better clinical improvement in schizophrenia patients. These often are heavy smokers attempting to treat negative and cognitive symptoms themselves. In a clinical trial investigating effects of transdermal nicotine patch, Chen et al. [14], however, found no correlation with replacement doses and only a low smoking cessation rate. They recommend more effective smoking cessation programs for this group of hospitalized patients. Due to restricted therapeutic effects of current treatment strategies in severe psychiatric disorders, the editorial A. Schmitt (&) P. Falkai Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nusbaumstr. 7, 80336 Munich, Germany e-mail: Andrea.Schmitt@med.uni-muenchen.de

Association of P1635 and P1655 polymorphisms in dysbindin (DTNBP1) gene with schizophrenia.

Schizophrenia (SCZ) is a severe psychiatric disorder with a lifetime prevalence of approximately 1% in most of the populations studied. SCZ is multifactorial with the contribution of multiple susceptibility genes that could act in conjunction with epigenetic processes and environmental factors. There is some evidence supporting the association between genetic variants in dysbindin (DTNBP1) gene and SCZ in populations. In this study, we investigated the association between polymorphisms P1635 and P1655 in dysbindin gene with SCZ. Totally, 115 unrelated patients with SCZ and 117 unrelated healthy volunteers were studied. Genomic DNA was extracted from blood. Genotyping was done with the PCR-RFLP method. The allele and genotype associations were analysed with X 2 test. The Benjamini-Hochberg procedure was used to correct p values for multiple comparisons. The results showed no significant difference between patients and controls in allelic frequencies or genotypic distributions of SNP P1635 (p = 0.809), but a significant difference between the case and control groups for SNP P1655 (p = 0.009) was found. We could also find a significant positive association between A-C haplotype and SCZ (OR = 1.7, 95% CI 1.18-2.42; p = 0.004, p c = 0.02) and a protective effect for A-G haplotype (p = 0.003, OR = 0.57, 95% CI 1.18-2.42; p = 0.003, p c = 0.02). This study may provide further support for the association between SNP polymorphisms in DTNBP1 and SCZ in the Iranian population. Studies with more markers and subjects for various populations will be necessary to understand the genetic contribution of the gene to the development of SCZ.

Structural and functional neuroimaging phenotypes in dysbindin mutant mice

Schizophrenia is a highly heritable psychiatric disorder that is associated with a number of structural and functional neurophenotypes. DTNBP1, the gene encoding dysbindin-1, is a promising candidate gene for schizophrenia. Use of a mouse model carrying a large genomic deletion exclusively within the dysbindin gene permits a direct investigation of the gene in isolation. Here, we use manganese-enhanced magnetic resonance imaging (MEMRI) to explore the regional alterations in brain structure and function caused by loss of the gene encoding dysbindin-1. We report novel findings that uniquely inform our understanding of the relationship of dysbindin-1 to known schizophrenia phenotypes. First, in mutant mice, analysis of the rate of manganese uptake into the brain over a 24-hour period, putatively indexing basal cellular activity, revealed differences in dopamine rich brain regions, as well as in CA1 and dentate subregions of the hippocampus formation. Finally, novel tensor-based morphometry techniques were applied to the mouse MRI data, providing evidence for structural volume deficits in cortical regions, subiculum and dentate gyrus, and the striatum of dysbindin mutant mice. The affected cortical regions were primarily localized to the sensory cortices in particular the auditory cortex. This work represents the first application of manganese-enhanced small animal imaging to a mouse model of schizophrenia endophenotypes, and a novel combination of functional and structural measures. It revealed both hypothesized and novel structural and functional neural alterations related to dysbindin-1.

Gene’s Link to Brain Abnormality May Be Schizophrenia Clue

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessGene’s Link to Brain Abnormality May Be Schizophrenia ClueJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:4 May 2012https://doi.org/10.1176/pn.47.9.psychnews_47_9_18-aAbstractNow that several genes have been linked to schizophrenia, and that disorder has been linked to various brain abnormalities, could the genes and the abnormalities be related?The evidence for that hypothesis is strong, at least for one of the more robust schizophrenia gene candidates— Dysbindin—a team of German scientists reported in the April NeuroImage. The lead researcher was Thomas Nickl-Jockschat, M.D., director of the Clinic for Psychiatry, Psychotherapy, and Psychosomatics at the University of Aachen.The study was based on 83 mentally healthy young subjects who were genotyped to see if they possessed either the C variant or the T variant of the Dysbindin gene. Forty-six were found to have two copies of the C variant, and 37 were found to have at least one copy of the T variant. An MRI-based imaging technique was used to evaluate white-matter structures in their brains. The scientists found that subjects who had the T variant of the Dysbindin gene—a variant linked to schizophrenia in previous studies—had white-matter abnormalities in the hippocampal region of the temporal lobe.Temporal-lobe abnormalities have been associated with core symptoms of schizophrenia, such as hallucinations and thought disorder. Thus it’s possible that if the T variant of the Dysbindin gene contributes to schizophrenia, it might do so by altering white matter in the hippocampal region of the temporal lobe, “although the molecular environment might be different in schizophrenia patients since we think of schizophrenia as a polygenic disorder,” Nickl-Jockschat told Psychiatric News.The T variant subjects were also found to possess abnormal white-fiber tracts in the frontal lobe, and reductions in frontal-lobe white matter have often been observed in people with schizophrenia.While the white-fiber abnormalities discovered in the T variant subjects were modest, it may be because the researchers examined healthy young subjects with a high level of intellectual functioning and without a history of psychiatric disorder in their first-degree relatives, they reasoned. Yet whether more pronounced white-matter abnormalities are present in individuals with schizophrenia or in their first-degree relatives remains to be determined, Nickl-Jockschat said.Interestingly, several mutations in the Dysbindin gene can cause X-linked muscular dystrophy, and neuropsychological abnormalities found in individuals with muscular dystrophy—essentially working-memory deficits—can also be found in individuals with schizophrenia.The study was funded by the International Research Training Group and RWTH Aachen University. An abstract of “The Impact of a Dysbindin Schizophrenia Susceptibility Variant on Fiber Tract Integrity in Healthy Individuals: A TBSS-Based Diffusion Tensor Imaging Study” is posted at www.sciencedirect.com/science/article/pii/S1053811911011736. ISSUES NewArchived

Poster #108 THE INFLUENCE OF DISC1 SER704CYS POLYMORPHISM ON THE CORTICAL THICKNESS OF SALIENCE NETWORK (INSULA AND ANTERIOR CINGULATE) IN PSYCHOSIS

s of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375 S319 Poster #107 EVIDENCE OF AN ASSOCIATION BETWEEN DYSBINDIN GENE AND AGE AT ONSET IN SCHIZOPHRENIA Kyuyoung Lee1, Eunjeong Joo1, Yongsik Kim2 1Department of Neuropsychiatry, Eulji University School of Medicine, Eulji General Hospital, Seoul, Korea; 2Department of Psychiatry & Behavioral Science and Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Korea Background: The dysbindin gene (DTNBP1) is located in chromosome 6p22.3, one of the regions of positive linkage for schizophrenia. In particular, dysbindin protein has been found to play a role in the glutatmate neural transmission in the brain. A strong genetic association between DTNBP1 and schizophrenia has been replicated through many recent studies. However, we have not replicated positive association between DTNBP1 and schizophrenia in our Korean sample. Because schizophrenia has been regarded as a disease with a quite heterogeneous origin and evolvement, it is useful to categorize patients with schizophrenia into relatively homogeneous subsets based on clinical characteristics including age at onset (AAO). Therefore, we investigated the association between DTNBP1 and AAOof schizophrenia. Methods: We assessed age at first occurrence of positive psychotic symptomsof 197 patients with schizophrenia. Four SNPs, SNPA, P1763, P1320 and P1655 of DTNBP1 were genotyped. Results: In SNPA, the patients with AT (N=10) showed significant earlier AAO than those with AA (N=187) (p<0.0001). The patients with heterozygote for SNP P1763 (TG, N=40) or P1320 (CT, N=41) also showed significant earlier AAO than those with homozygote (P<0.0001, P<0.0001, respectively). However, in SNP P1655, there was no significant difference of AAO between genotypes. Discussion: In conclusion, although we were unable to support an association between DTNBP1 and schizophrenia, DTNBP1 might play a role in disease-modifying. However, considering the several limitations of this study, further research involving different polymorphisms in DTNBP1and various clinical subsets with sufficient numbers will be required to evaluate the contribution of DTNBP1 to schizophrenia. Poster #108 THE INFLUENCE OF DISC1 SER704CYS POLYMORPHISM ON THE CORTICAL THICKNESS OF SALIENCE NETWORK (INSULA AND ANTERIOR CINGULATE) IN PSYCHOSIS Lena Palaniyappan1, Vijender Balain1, Molly Simmonite1, Liam Carrol2, Peter McGuffin2, Katherine Aitchison2, Peter F. Liddle1 1Division of Psychiatry, University of Nottingham, Nottingham, England, United Kingdom; 2MRC SGDP, Institute of Psychiatry, Kings College, London, England, United Kingdom Background: Psychosis is characterized by significant reduction of grey matter in anterior cingulate cortex (ACC) and the insula. An emerging literature has demonstrated an association between the Disrupted-inSchizophrenia 1 (DISC1) gene and the development of cortical grey matter. Allelic variation at rs821616 (Ser704cys) has been associated with both structural and functional changes in psychosis. Our objective was to examine the relationship between grey matter reduction salience network sites (ACC/Insula) and Ser704cys variation in psychosis. Methods: High-resolution anatomical scans were obtained from 45 subjects (23 with psychosis and 22 healthy individuals with 10 cysteine carriers in each group). We employed cortical surface based analysis using Freesurfer (v5.0) to measure cortical thickness and surface area. Various cortical regions were parcellated using Destrieux atlas, and the regions constituting the insula (short and long gyri) and anterior cingulate were included for further analysis. Results: We detected a significant omnibus interaction effect between diagnostic status and genotype for cortical thickness (F(1,38)=5.071, p=0.03). Among cysteine non-carriers, a highly pronounced diagnostic difference was noted in the adjusted mean thickness (patients = 3.014mm, controls = 3.254mm, t=3.54, p=0.002). Such a diagnostic difference was not noted in cysteine carriers (patients = 3.122mm, controls = 3.139mm, t=0.23, p=0.83). Among patients, a significant difference was also noted between the two genetic groups in terms of levels of functioning measured using Social and Occupational Functioning Scale (total SOFAS score: cys non-carriers = 47.54; carriers = 59.10, F=6.07, p=0.02) and symptom burden measured using Signs and Symptoms in Psychotic Illness scale (total SSPI score: cys non-carriers = 13.46; carriers = 8.10, F=2.71, p=0.11). The polymorphism was not associated with effects on the cortical surface area of ACC/Insula. Discussion: Our findings suggest that morphometric changes associated with psychosis are influenced by the polymorphic variation in DISC1, which plays a cardinal role in regulating neuronal migration. The pathoplastic effect of DISC1 in psychosis is likely to be mediated by the structure of grey matter in the Salience Network. Poster #109 HISTORICAL STUDY OF INFLUENCE OF NON-GENETIC FACTORS ON TWIN CONCORDANCE FOR SCHIZOPHRENIA