S-08-01

Functional candidate genes in schizophrenia: Findings from animal models

D. Rujescu, A. Bender, M. Keck, A. M. Hartmann, F. Ohl, H. Raeder, I. Giegling, J. Genius, R. Greene, H.-J. Möller, H. Grunze. University of Munich Dept. of Psychiatry, Munich, Germany

The psychotomimetic effects of noncompetitive N-methyl-Daspartate (NMDA) receptor antagonists such as PCP and ketamine in healthy humans and their ability to exacerbate several psychotic symptoms in schizophrenic patients have promoted a view of schizophrenia as being related to an altered ghitamatergic neurotransmission. This prompted us and others to develop animal models for schizophrenia. Attempts to mimic these effects in rats has lead to the recognition of parallels between schizophrenia and molecular, cellular, functional and behavioral abnormalities in these animal models. In our model, chronic, low-dose treatment with the NMDA receptor antagonist MK801 alters the expression of NMDA receptor subunits in a pattern similar to schizophrenia on the molecular level. On a cellular level, the number of parvalbumin- but not calretinin-positive intemeurons was selectively decreased, a finding which parallels observations in post mortem brain from schizophrenic patients. On a functional level, recurrent inhibition of pyramidal cells was altered, as postulated from the histological findings. Finally, on a behavioral level, these animals showed cognitive deficits like disturbed working memory, which again parallels findings in schizophrenia. Thus, our pharmacologic model of NMDA receptor hypofunction has a significant potential as an animal model of psychosis-related phenotypes and as a tool in the identification of candidate genes for this disorder. We used a functional genomic approach for the identification of hippocampal candidate genes for psychosis-related traits and identified several differentially expressed genes and pathways. These are under investigation in ongoing genetic analyses.

S-08-02

Genetic association studies in schizophrenia

M. Gennarelli. Genetic Unit, 1RCCS Centro S., Brescia, Italy

Objective: Although schizophrenia is a genetic disorder with estimates of risk heritability of around 80%, the identification of susceptibility genes, which act in concert with epigenetic processes and environmental factors, remains an uphill struggle. Genetic association studies have focused initially on the neurochemical theories of schizophrenia detecting, as putative functional candidates, dopamine and serotonin system-linked genes. The feasible association with DRD3 and 5-HT2A receptor genes implies most likely an involvement of other neurotransmitter pathways. A role of glutamatergic signalling in the pathogenesis of schizophrenia has been suggested by the recent identification of five susceptibility genes (NRG1, DTNBP1, COMT, RGS4, G72), alltogether implicated in interlinked processes at glutamate synapses. These promising results come from positional approach and animal models data confirmed with the genetic association studies. Thus, these studies are useful to confirm the role of "candidate" genes based on map or pre-clinical findings but represent the more direct method to test other "candidate" aetiopathological hypotheses. Additional susceptibility genes are emerged fxom this approach, such as those linked to brain development (BDNF, GDNF, GSK-313) and to cytokine network (IL-1, TNFa, IL-10). It was only to be expected, these association studies are characterised by a constellation of replica and nonreplica of data because they suffer of some notorious limitations. New methodological strategies are in progress to overcome these limitations improving the reliability of these studies.

S-08-03

Linkage studies in schizophrenia: New findings promise new insights

M. Owen. Dept. of Psychological Medicin, Cardiff, United Kingdom

Objective: Genetic epidemiological studies suggest that individual variation in susceptibility to schizophrenia is substantially genetic. However, like other common disorders, the mode of transmission is complex and probably reflects oligogenic inheritance against a polygenic background.

Methods: Genomic approaches to schizophrenia are becoming increasingly feasible as data from the genome project accumulate and technology improves. Attempts to identify genes for schizophrenia have been based on several approaches; systematic linkage studies, association studies and studies of chromosomal abnormalities associated with the disorder.

Results: As larger samples have been studied, a number of relatively convincing linkages have been reported. Moreover analysis of these chromosomal regions has revealed evidence in favour of several positional candidate genes. This evidence now strongly implicates DTNBP 1 and NRG 1 as susceptibility genes for schizophrenia, while the data for DAO, DAOA, DISC1 and RGS4 are promising. However, there are reasons to remain cautious pending the results of further genetic and biological studies.

Conclusion: The positive findings potentially converge upon abnormalities in glutamatergic neurotransmission in schizophrenia, for which evidence from a number of other sources has already been adduced. However, there are other possible explanations and more work is needed to elucidate pathogenic mechanisms.

S-08-04

The impact of first schizophrenia genes: Focus on dysbindin

W. Maier. Department of Psychiatry, Univ, Bonn, Germany

The first disposition genes for schizophrenia were identified and replicated in 2002 and 2003: for dysbindin, for neuregulin 1, and for G72/G30. These major break-through became possible after genome-wide linkage analyses delineated candidate regions (among them intervals on chromosome 6p, 13q, 8p) which were likely to cover disposition genes. Linkage disequilibrium mapping in these regions was able to identify these three genes. Further candidate regions affirmed in recent metaanalyses, are under intensive study in order to identify additional disposition genes. Although disposition genes are identified, the search for pathogenic mutants is more difficult than expected. Up to now, only associations between haplotypes in these genes and the disorder are replicated, but the pathogenic mutant is not identified for any disposition gene. Yet, genotype-phenotype relationships can also be explored for at-risk haplotypes in disposition genes. We report the first associations between at-risk haplotypes of the dysbindin gene (DTNBP1) and brain structure and function in schizophrenia.