The dopamine hypothesis remains a prominent influence on research into the pathophysiology of schizophrenia (SCHIZ), yet the presence of consistent SCHIZ-linked abnormalities either in the presynaptic components of the dopamine system or in dopamine receptors (DRs) still remains a matter of debate. The present proposal focuses on a recently recognized group of DR-interacting proteins (DRIPs) as possible novel sites of dysfunction in SCHIZ. In pursuing this hypothesis, we have already demonstrated that the dorsolateral prefrontal cortex from SCHIZ cases of the Stanley Foundation Neuropathology Consortium express significantly increased levels of the D 1 DRIP, calcyon, and the D2 DRIP, NCS-1. These findings support our proposition that SCHIZ is associated with altered levels of specific DRIPs. It is also interesting that these two proteins strongly associate with Ca2+ signaling. Therefore, they have joined the growing list of molecules involved in Ca2+ signaling and whose abnormalities have been reported in SCHIZ. Consequently, our data uphold the central hypothesis of our Center that SCHIZ, while may be induced by multifactorial causes, is, at its core, a disease of Ca2+ signaling. The main goal of this project is to confirm and expand our examinations of DRIPs in SCHIZ, which is essential for proving both the specific hypothesis of this project and the general hypothesis of the entire Center. This will be achieved in the following specific aims: 1. We will determine whether in SCHIZ patients levels of calcyon and NCS-1 are affected in areas other than the previously-examined dorsolateral prefrontal cortex. We will also examine whether the changes in these DRIPs could be consistently observed in samples from several brain collections. 2. We will determine whether detected changes in levels of calcyon and NCS-1 proteins are associated with increased transcription of these DRIPs by regional cells. 3. We will analyze possible SCHIZ-linked changes in the proportion of calcyon- and NCS-1-containing neurons and glia among the cells of specific brain regions and their structural subdivisions. 4. We will conduct a detailed examination of the cellular and subcellular distributions of calcyon and NCS-1 in specific regions of the primate brain. 5. We will continue to evaluate additional novel DRIPs.
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