DISC1-dependent defects in neural fate, corticogenesis and cognition in psychosis

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DESCRIPTION (provided by applicant): The diagnostic boundaries defined by current diagnostic systems (e.g., DSM) are now being challenged by recent advances in the genetic architecture underlying psychiatric disorders. Meanwhile, NIMH has launched the Research Domain Criteria project (RDoC) to develop, for research purposes, new ways of classifying psychopathology based on dimensions of observable behavior and neurobiological measures beyond the current diagnostic systems. The DISC1 gene was originally discovered as the sole disrupted transcript with an open reading frame, at the breakpoint of an inherited chromosomal translocation in a Scottish pedigree: it segregates with a variety of major mental illnesses, including schizophrenia (SZ), bipolar disorder (BP), and major depression. Nonetheless, genome wide association studies have failed to detect associations between DISC1 locus and SZ (or other DSM-categorized diseases thus far). In contrast, the data from association studies of DISC1 with anatomical, physiological, and behavioral traits, which commonly underlie the pathology of major mental illnesses, have been promising. Thus, we hypothesize that DISC1 is a promising target to address mechanisms underlying mental illnesses across diagnostic categories in the RDoC framework: DISC1 may be a good probe that mediates translation from the discoveries in basic genetics, neuroscience, and behavioral science into clinical application. Based on our preliminary data, we further hypothesize that a decrease in the level of phosphorylation at serine-713 of human DISC1 (pS713-DISC1) underlies delayed neural differentiation, which disturbs neural circuitry formation in the brain development and, in turn, interferes with the acquisition of working memory. We will study relatively stable outpatients with SZ and BP, as well as well-matched healthy controls. Within the RDoC framework, our construct of interest is working memory (cognitive domain), whereas the independent variable is pS713-DISC1 (molecule). Our dependent variables include neuronal fate (cells), cortical surface area, thickness, and volume (circuit), and working memory (behavior). Johns Hopkins Schizophrenia Center has established an infrastructure of translational research in which we conduct clinical/neuropsychological assessment, brain imaging, and multiple tissue biopsies for molecular and cellular study simultaneously from each study participant. This infrastructure allows us to perform experiments in which molecular, anatomical, and behavioral data will be obtained from the same individuals. By utilizing this potential strength, we will address how behavior and neuroanatomical abnormalities relevant to psychotic disorders (SZ and BP currently categorized by DSM) are quantitatively associated with a specific molecular signature (phosphorylation of DISC1 in this study).