SCHIZOGENES

Role of genetic interaction between COMT and Dysbindin in cognitive and schizophrenia-related abnormalities

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'Cognitive deficits are common in most brain disorders and are characteristic of schizophrenia, which is among the most debilitating and costly diseases. Genetic association studies have implicated several potential schizophrenia-susceptibility genes, but a direct genetic cause/mechanism remains elusive. Schizophrenia is dependent upon dysregulation of the dopaminergic system, particularly in the prefrontal cortex (PFC). Catechol-O-methyltransferase (COMT) and dysbindin (dys) are two potential schizophrenia susceptibility genes which regulate cortical dopamine signaling and impact cognitive function. Schizophrenia is likely related to the combined malfunction of multiple genes rather than a single gene mutation. Genetic modifications resulting in selective reduction of either COMT or dys increase dopamine signaling in the PFC. Thus, we predicted that combined COMT*dys reduction in the same individual would demonstrate epistatic interaction between these genes through excessive cortical dopamine signaling. We are accumulating evidence in humans indicating that combined COMT and dys hypomorphisms is strongly associated with schizophrenic phenotypes and cognitive deficits. Therefore, we generated a COMT*dys double null mutant mouse (COMT*dys) which we propose to study for schizophrenia-like phenotypes. Because deficits in executive functions are at the core of schizophrenia, we aim to identify the specific cognitive domains affected by COMT*dys genetic interaction. Additionally, we shall investigate the neurophysiological correlates of such dysregulated behaviors in COMT*dys mice. In a therapeutic prospective, based on the recognized COMT/cannabinoids/schizophrenia interplay, we shall focus on the cross-talk between dopamine- and cannabinoid-mediated signaling in brain regions related to executive functions. This approach will shed light on specific genetic and cellular mechanisms contributing to psychiatric and cognitive abnormalities.'

Introduzione (Teaser)

Scientists carried out an in-depth investigation into two potential schizophrenia susceptibility genes. They successfully identified key mechanisms contributing to schizophrenia, a debilitating and costly psychiatric disorder.

Descrizione progetto (Article)

To provide mechanistic insights into cognitive abnormalities and schizophrenia-related phenotypes, European researchers built on earlier related work through the EU-funded SCHIZOGENES (Role of genetic interaction between COMT and Dysbindin in cognitive and schizophrenia-related abnormalities) project.

The team developed a suite of innovative tasks with high translational validity for human studies. They probed the effects of memory load and environmental changes and automatically dissected different aspects of attentional control in mice. A machine-learning-based system was able to finely analyse social cognition and behaviours, which are key altered features in human patients affected by schizophrenia.

Under examination were the two susceptibility genes, catechol-O-methyltransferase (COMT) and dysbindin (dys). In schizophrenia, the dys-1 gene acts as a bridge between the changes in the dopaminergic and glutamatergic systems. Interestingly, COMT and dys genes interact and a reduction in expression in any one of them produces memory advantages. Cutting expression in both genes however yields memory deficits.

Modification of COMT can modulate attention, impulsivity, stress reactivity, compulsivity, flexibility and motivation, depending on gender and different environmental factors. Genetic reduction of COMT transcription improved selective attention switching between different perceptual dimensions but impaired serial reversal learning.

Researchers were also able to predict genetic-driven phenotypes in humans using mouse models. The reduction in COMT enzyme was accompanied by a thickening of the prefrontal cortex (PFC) of healthy human males but not females. Gender also influenced genotype effects in cognitive functions like working memory. Moreover, COMT-dys gene interaction affected PFC-related behaviours in humans.

Dissemination of SCHIZOGENES results includes publications, lectures, poster presentations at national and international meetings, and securing grants for further work. Presentation of scientific discoveries at national and international meetings has enabled knowledge sharing with other European laboratories. Project work has thereby contributed to the European Research Area and boosted the transfer of resources and knowledge slated to benefit neurophysiological research.

SCHIZOGENES data has contributed to a knowledge platform on specific genetic mechanisms that contribute to psychiatric states such as schizophrenia. Identification of groups of humans with the relevant genetic profiles as indicated in the study will direct research for more effective therapeutic strategies.