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.
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