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Deciphering inter- and intracellular signalling in schizophrenia

Final Report Summary - IN-SENS (Deciphering inter- and intracellular signalling in schizophrenia)

The science of MSCA-ITN IN-SENS is concerned with "Inter -and intracellular signalling in schizophrenia" and, particularly, in shuttling insights from clinical psychiatry to basic science, and back from basic science into clinical psychiatry. MSCA-ITN IN-SENS is an ESR training network that has educated the next generation of researchers in the field of molecular and translational psychiatry, as well as neurosciences related to behavioural control. Schizophrenia is a chronic disease with a plethora of so-called positive symptoms (delusions, hallucinations), negative symptoms (lack of drive and affect), as well as cognitive symptoms (working memory and attention deficit).

A salient problem in the field of schizophrenia research is that „schizophrenia“ is a merely clinical diagnosis without the possibility of the use of assisting „objective“ tests, as in other medical diagnoses. This is due to a lack of understanding of the underlying biology. One of the main problems is that the underlying causes of the heterogenous subsets are not clear. One of the goals of IN-SENS was therefore to identify and characterized biological subsets of disease, but also to recognize converging pathways leading to similar phenotypes.

The network started with several established molecular, cellular and animal models. In particular model systems around the Disrupted-in-schizophrenia 1 (DISC1) gene and protein were investigated in depth, but also compared to other models. Aberrant proteostasis, i.e. the proper maintanance of protein concentrations in a functional state, is a hallmark of chronic brain diseases and therefore likely to exist in schizophrenia, too. We conducted a global study on proteostasis in post mortem brains form patients with schizophrenia and discovered novel protein candidates that will help reveal an underlying biology. We had already identified the DISC1 protein as being insoluble in a subset of cases of schizophrenia, and, to model this disease subset in vivo, generated a transgenic rat that overexpresses the non-mutant DISC1 protein and generates insoluble DISC1 proteins in the brain. This model was used for extended behavioural tests that revealed aberrant attention and long term memory, and also aberrant place cell coordination in the hippocampus of these animals. Together with an identified aberrant dopamine homeostasis this means that this animal model is face valid in representing key traits of patients with schizophrenia. In a reverse translational approach we identified specific biomarkers in the blood of these animals that were backtranslated into two independent patient cohorts and could identify a large subsets of patients. Provided that these experiments can be repeated in yet larger cohorts this means that a first blood test for a subset of cases with schizophrenia could be identified and validated.

Clinical studies could confirm a role of DISC1 in the dopamine synthesis capacity of patients when it was shown that a polymorphism in DISC1 that is disease-associated in genetic studies led to an increase dopamine capacity which is a phenotype of patients with schizophrenia.

DISC1 is linked to a network of proteins and genes that, independently, have also been asosciated with mental illnesses suggesting that there may be converging pathways in mental illness. In this context the role of the secreted protein VGF was investigated that is downregulated in DISC1 knockout models and has independently been reported to mediate anti-depressant effect. Candidate receptor proteins for VGF were identified that may represent future, novel pharmacological targets. The DISC1 network was investigated on a genetic level in Finnish families and a network could be extended to NDE1, PDE4D and ANK3 genes. These have potential functional consequences, such as variants located in regulation elements, or are amino acid changing.

Using proteomic techniques from immunoprecipitation experiments an extended DISC1 interactome was determined and a critical role of a network of genes was also determined in experiments functionally. The role of the synpase as a converging point of schizophrenia was further investigated by automated high-content confocal microscopy, and comparison to neuronal cells from other animal models of brain disease in a systems biology framework. In the high content impaging approach five genes reported to be DISC1 interactors (FEZ1, PCM1, NDEL1, CIT, PDE4D) were identified. The knockdown of those genes gave an increase in neurite length and neurite arborisation, similar to, but not as pronounced as, after knocking down DISC1 itself. Evidence suggests that these proteins form one large multiprotein complex with a key role in schizophrenia pathogenesis.

In addition, common behavioural signatures of several transgenic mouse models mimicking human microdeletion mutations was investigated. Three mouse models carrying hemizygous microdeletions syntenic to Schizophrenia-associated CNV in humans showed behavioural changes in specific behavioural domains, i.e. executive function (22q11), social behaviour (15q13) and sensorimotor gating (22q11 and 15q13). Moreover, the role of the prefrontal parvalbumin interneurons in attention and impulsivity in mice was studied using new chemogenetic tools, i.e. the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Preliminary results showed an involvement of these cells in attentional performance in an automated version of the Five-Choice Serial Reaction Time Task (5-CSRTT).

In summary, we have worked on cell and animal models as well as on genetically well-defined subsets of patients with schizophrenia and advanced the characterization neurobiology of these subsets. IN-SENS has trained its ESRs in a wide range of new techniques, scientific excellence and independency and spent a lot of training to acquire transferable skills so that the IN-SENS ESRs are well equipped for industrial jobs and that they can strengthening this so far neglected area in European research.
Contact Prof. C. Korth: