changes in mediators of GABA neurotransmission are altered in celltype-, lamina- and circuit-specific fashions in the PFC of individualswith schizophrenia. The utility of these findings for the identifica-tion of novel drug targets to improve cognitive dysfunction inschizophrenia, and for the use of such drugs in both personalizedand pre-emptive interventions, will be presented.

doi:10.1016/j.schres.2010.02.006

NOVEL ANIMAL MODELS FOR STUDYING SCHIZOPHRENIA:BAC-DRIVEN MIRNA-MEDIATED IN VIVO SILENCING OFGENE EXPRESSION

Karoly MirnicsVanderbilt University, Nashville, TN, USA

In schizophrenia, GAD1 disturbances are robust, replicable andrepresent a core feature of the disease, making it a leadingcandidate for developing transgenic animal models that mimicthe disease phenotype. However, GAD1 downregulation in theprefrontal cortex is not uniform across all the interneuronalsubpopulations: parvalbumin- (PARV), somatostatin- (SST) andNPY-containing neurons appear to be preferentially affected in acomplex pattern. Importantly, neuropeptide Y (NPY), a phenotypicmarker of a subpopulation of GAD1-containing interneurons, hasshown reduced expression in the PFC in subjects with schizo-phrenia, suggesting that dysfunction of the NPY+ cortical inter-neuronal subpopulation might be also a core feature of thisdevastating disorder. To mimic these postmortem findings, wegenerated a transgenic mouse in which we down-regulated GAD1mRNA expression specifically in NPY+ neurons. This novel, celltype-specific in vivo system for regulation of gene expressionutilizes a bacterial artificial chromosome (BAC) containing the NPYpromoter-enhancer elements, the reporter molecule (eGFP), and amodified intron containing a synthetic miRNA targeted to GAD1.Furthermore, due to incorporation of an eGFP coding sequence, thetargeted cells are identifiable in both live and fixed tissue. Theadvantages of this in vivo gene silencing system are numerous, andinclude cell-type specific downregulation of transcripts, visualiza-tion of the targeted cells by eGFP, low cost and rapid generation andmonoallelic inheritance. Finally, due to the small size of thesilencing miRNAs, this method may allow targeting of specificsplice-variants, generating splice-variant specific knockdown ani-mals. Combined analysis of the NPY-, PV-, CCK-, and SST-BAC driven,GAD1 miRNA silenced mice (which are currently in production inour laboratory) will greatly contribute to our understanding themechanisms by which different interneuronal subpopulationsmediate cortical inhibition, working memory and cognition. Finally,this knowledge will help us understand the relationship betweenthe cell-type specific GABA-ergic disturbances and the phenotypicmanifestations of schizophrenia.

doi:10.1016/j.schres.2010.02.007

EPIGENOME MAPPING IN DEVELOPING AND DISEASEDPREFRONTAL CORTEX

Schahram AkbarianUniversity of Massachusettes Medical School, Worcester, MA., USA

Alterations in chromatin structure and function, includingchanges in levels or distribution of histone lyine methylation

markings and other epigenetic regulators of gene expression couldaffect neuronal signaling in schizophrenia and other majorpsychiatric disease. However, to date, nothing is known about theregulation of neuronal and other cell-type specific epigenomes inhuman or animal brain. Here, we provide first insights into thegenome-wide distribution of trimethylated histone H3K4(H3K4me3), a histone mark associated with actual or potentialtranscription, in neuronal nuclei collected postmortem fromprefrontal cortex (PFC) across a wide age range (0.5-70 years).Massively parallel sequencing identified 16,000-22,000 H3K4me3enriched regions (peaks), the majority located proximal to (within2 kb of) the transcription start sites (TSS) of annotated genes. Theseincluded signatures specific to neurons as well as signatures specificto individual subjects. Preliminary findings reveal age correlatedgenome reorganization in the postnatal PFC, including a generalincrease in TSS-associated H3K4me3 peaks concomitant with loss ofpeaks at many developmentally regulated genes. In addition,H3K4me3 mappings in PFC neurons from subjects with schizo-phrenia and matched controls, and histone methyltransferasemutant mice, are in progress. We predict that epigenome mappingin defined cell populations of the human brain, in conjunction withRNA and transcriptome profiling in diseased tissue and preclinicalmodel systems, will uncover novel mechanisms governing normaland diseased neurodevelopment. Schahram Akbarian, Iris Cheung,Hennady P. Shulha, Zhiping Weng Brudnick NeuropsychiatricResearch Institute and Program in Bioinformatics and IntegrativeBiology, University of Massachusetts Medical School, Worcester,MA, USA Acknowledgments: Postmortem tissue was provided byBTB Dev. Dis., U.M. (Dr. R. Zielke), UC Irvine and Davis (Dr. W.E.Bunney Jr., Dr. E.G. Jones), MPRC (Dr. A. Lessard; Dr. R. Schwarcz),HBTRC (Dr. F.M. Benes) and Bronx VA (Dr .H. Haroutunian).Supported by the National Institute of Mental Health(5RC1MH088047 and 5R01MH071476) (S.A.), the National ScienceFoundation DBI 085008 (Z.W.), IMHRO and NARSAD.

doi:10.1016/j.schres.2010.02.008

ERBB4 AND PI3KCD AND ARE INTERACTING BIOLOGICALAND GENETIC FACTORS THAT REGULATE NRG1-MEDIATEDPI3K SIGNALING AND RISK FOR SCHIZOPHRENIA

Amanda LawNIMH, Bethesda. MD., USA

Background: The identification of variations in DNA that increasesusceptibility to disease is one of the central aims of humangenetics. However, classical genetic approaches, whilst identifyingsusceptibility loci, provide little information as to how the genesrelate to the disease. Here we provide a systems biology approachutilizing molecular, cellular and clinical genetic investigations tointerrogate interacting gene networks and biological pathwaysdownstream of main effects of DNA variation in the ErbB4 gene thatassociate with schizophrenia. Using cell and molecular biology wehave uncovered a specific downstream target of NRG1 activation inrelation to ErbB4 genetic risk, the PI3-kinase gene-PI3KCD. Weshow that in addition to alterations in PI3KCD expression andfunction of the PI3K system in human lymphoblastoid cell lines andthe human brain, PI3KCD is linked with risk for schizophrenia intwo independent family-based association studies and showsepistasis with ErbB4. We propose that altered NRG1/ErbB4 signalingrepresents an upstream effector of altered PI3K function inschizophrenia, mediated via PI3KCD.Methods: PI3KCD expression, PI3K intracellular signaling and cellmigration were measured in lymphoblasts from patients withschizophrenia and normal controls in relation to genetic risk

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variation in ErbB4 (Haplotype rs7598440, rs707284, rs839523).PI3KCD expression phenotypes were also examined in the humanbrain in the disease. Tag SNPswere selected in PI3KCD alongwith anycoding variations in the NCBI database. 20 SNPs were genotyped inthree independent clinical samples, two family based and one case-control. Main effects analyses of single SNPs and haplotypes wereconducted using unconditional logistic regression in the case-controlsamples and using the family-based association test (FBAT) infamilies. Epistasis between DNA variants in ErbB4 and PI3KCD weretested in both the case-control and family samples using uncondi-tional and conditional logistic regression. Results: Disease state andthe ErbB4 risk haplotype were associated with differential expres-sion of a PI3KCD/p55gamma complex in lymphocytes, downstreamof changes in ErbB4 splice gene expression and upstream of alteredNRG1-mediated intracellular PIP3 signaling and NRG1-induced cellmigration. At the clinical genetic level, we report distortedtransmission of SNP alleles in PI3KCD in two independent family-based samples and epistasis between ErbB4 and PI3KCD.Discussion: Our results provide direct experimental and geneticevidence that complex diseases such as schizophrenia are emergentproperties of interacting molecular networks modified by geneticloci. Variation in expression of the ErbB4 gene in relation to risk forschizophrenia has downstream functional consequences for thePI3K pathway at both the molecular and cellular phenotype level. Asystems biology approach to elucidating the architecture ofaberrant signaling networks in schizophrenia in relation to geneticrisk has significant value for the identification of novel risk genesand for the development of new targeted therapeutics.

doi:10.1016/j.schres.2010.02.009

DISC1 PATHWAY EXPRESSION IN MOUSE AND MAN

David PorteousUniversity of Edinburgh, Edinburgh, UK

Background: DISC1 is nowwell established as a genetic risk factor fora range of major mental illnesses, mediated through the role of DISC1as a hub protein which interacts with multiple binding partners toregulate neurodevelopment and neurosignalling pathways. MethodsHere, we describe the outcome of transcriptional profiling studies inthe following experimental contexts: 1. Comparative analysis of fetaland adult brain expressionprofiles in theQ31L and L100PDisc1mouselines and the effect of behaviour modifying drug treatment in theL100P Disc1 line. 2. Transcriptional profiles of human lymphoblastoidcell lines with and without the t(1;11) translocation which disruptsDISC1. 3. The effect of common SNP variants of DISC1, PDE4 and NDE1on transcriptional profiles of human lymphoblastoid cell lines. Results1. GO Tree analysis of differentially expressed genes found over-representation of cell-cell signalling, transmission of nerve impulses,synaptic transmission, neurotransmitter secretion, vesicle dockingduringexocitosis andperipheralnervous systemdevelopment, overlapwith schizophrenia-associated CNV loci and independent DISC1pathwayanalyses. 2. The effect of the t(1;11) is to dysregulatemultiplesignalling pathways. Genes showing significantly altered expressioninclude candidate SZ/Autism genes and synaptic genes. 3. Disc1pathway variants selectively modulate the expression of cytoskeletal,synaptogenetic, signalling and sensory perception genes. The Disc1regulome is enriched for proteins that are current targets forpsychiatric drug development. Conclusions In addition to the directeffects of DISC1 interaction with protein partners, the DISC1interactome, common variants and rare mutations in DISC1 directlyand indirectly affect global patterns of expression. These DISC1 relatedtranscriptional profiles may serve as useful central and peripheralbiomarkers of disease and response to treatment. Sarah Brown1,

William Hennah1,2, Christoph Grunewald1, Xu Tang1, L. MiguelCamargo3, Steven Clapcote1,4, Kirsty Millar1 Pippa Thomson1, KathyEvans1 & David Porteous1 1Medical Genetics Section, University ofEdinburgh Molecular Medicine Centre and Institute of Genetics andMolecular Medicine, Edinburgh EH4 2XU, UK. 2Institute for MolecularMedicine Finland, National Institute for Health and Welfare, Biome-dicum Helsinki, FI-00251, Finland 3Merck Research LaboratoriesBoston, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. 4Instituteof Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT,UK.

doi:10.1016/j.schres.2010.02.010

Special SessionPSYCHOSOCIAL SESSION - AN UPDATE ON PSYCHOSOCIALTREATMENT OF SCHIZOPHRENIAChairperson: Kim MueserSunday, 11 April, 2010 - 1:30 pm - 3:30 pm

Overall Abstract: Significant advances have been made over thepast several years in the psychosocial treatment of schizophrenia.This symposium brings together international experts who willprovide an update on recent developments in cognitive behavioraltherapy for psychosis, family psychoeducation, assertive commu-nity treatment, vocational rehabilitation, cognitive remediation, andsocial skills training. In addition, the symposium will describe tworecently funded projects by NIMH that are developing andvalidating first episode psychosis programs designed to beimplemented in the U.S. healthcare system.

doi:10.1016/j.schres.2010.02.011

FIRST EPISODE PSYCHOSIS AND ASSERTIVE COMMUNITYTREATMENT

Lisa DixonUniversity of Maryland School of Medicine, Baltimore, MD, USA

Avariety of team-based approaches have proven to be effective forthe care of persons with schizophrenia. Assertive CommunityTreatment (ACT) is an established evidence-based model. The mostrecent Schizophrenia Patient Outcomes Research Team (PORT) reviewrecommended ACT on the basis that it reduces hospitalization andhomelessness. When compared to standard community care, Co-chrane reviews have found that those receiving ACT were more likelyto remain in contact with services, were less likely to be admitted tohospital. and spent less time in hospital. Those receiving ACT also hadmore favorable accommodation status, employment and patientsatisfaction. Recent attempts to focus on substance abuse and assistingforensic populations have yielded mixed results suggesting that morework is necessary to understand how to extend and focus ACT'seffectiveness. Multi-element team-based models analogous to ACThave also been tested in the care of individuals with recent onset ofschizophrenia. Studies conducted in Europe and Australia havesuggested a range of possible benefits of team basedmodels includingreduced symptoms, substance abuse, treatment retention, and socialand occupational functioning. One of the US NIMH-funded RecoveryAfter an Initial Schizophrenia Episode (RAISE) initiatives developed bythe Research Foundation for Mental Health team (Lieberman, PI,Dixon, Co-PI) will employ a team-based approach that builds onprinciples of ACT, Critical Time Intervention(CTI)models, andprevious

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