DOPAMINE - Dysbindin genetic interaction: a multidisciplinary approach to characterize cognitive phenotypes of schizophrenia and develop personalized treatments

Schizophrenia is a disabling disorder that seriously affects patients and their families’ daily lives.
The etiology of schizophrenia is complex and largely unknown, with a strong genetic contribution. While several potential schizophrenia-susceptibility genes have been identified, their effects are small and replication remains difficult, likely because of the complexity of the disease, genetic and clinical heterogeneity and the potential impact of gene-gene interactions. In this context, DTBP1 (Dysbindin, Dys) and the dopamine D2-like receptors (D2R and D3R) are three leading candidate susceptibility genes for schizophrenia. In particular, they are all implicated in the regulation of dopamine signaling that plays a key role in the pathophysiology and treatment of schizophrenia. Dys gene expression and its protein levels are reduced in patients with schizophrenia and genetic variants reducing dys expression impair cognitive abilities, probably as a consequence of an up-regulation of D2-like receptors on the neural surface in brain areas associated with schizophrenia. Therefore, the study of DTNBP1, D2R and D3R and their functional interaction is fundamental for the identification of the mechanisms involved in the pathogenesis of schizophrenia and response to treatments. However, these interactions have not been studied yet leaving an important gap in knowledge. This project will assess the functional interactions among dysbindin, D2R and D3R through a multidisciplinary approach combining preclinical studies and neuroimaging/genetic studies in healthy volunteers and patients with schizophrenia. Special emphasis will be placed on cognitive abnormalities, since they are core-enduring symptoms in schizophrenia, dramatically contributing to poor functional outcomes in patients and currently representing a great “unmet therapeutic need”. Thus, findings from this project can contribute to the development of effective tools (e.g. genetic testing) to provide personalized treatments, improving response rates, and identify new therapeutic targets.
The preclinical part of the project will study behavioral and neuronal alterations involved in the neurodevelopment of dysbindin, D2R and D3R knockout mice and double knockouts D2R*Dys and D3R*Dys (U1/Drago). In this context, mutant mice bearing selective mutations of schizophrenia-susceptibility genes are unique tools to elucidate the neurobiological basis of this disabling disorder. In these models, we will also study the molecular, proteomic and electrophysiological modifications induced by the acute and chronic administration of antipsychotics (U1/Drago, U2/D’ascenzo and U3/Tascedda), to investigate the biological mechanisms of drug response. From a translational point of view, in silico models will be used to study both the genetic co-expression network of DRD3 and to identify polymorphisms involved in the control of the expression of these genes that will be used to calculate a polygenic score (U4/Pergola). The neural effects of the DRD3 co-expression network will be investigated using morphological and functional neuroimaging on healthy subjects (U5/Sambataro). Finally, results from previous project phases will be validated and expanded with a genetic case-control and pharmacogenetic study in patients with schizophrenia (U6/Serretti).
The combination of these pre-clinical and clinical complementary approaches represents the first attempt to study the interactions between Dysbindin, D3R and D2R genes, which will provide new insights into the pathogenetic mechanisms of schizophrenia, contribute to the biological characterization of phenotypes of the disease and the mechanisms of antipsychotics response. This last objective can allow the development of personalized treatments and the identification of novel pharmacological targets.