D3 pre-mRNA processing in chronic psychosis

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DESCRIPTION (provided by applicant): In brains of patients with chronic psychosis, an abnormally increased alternative splicing of dopamine D3 receptor-encoded pre-mRNA leads to a significant decrease in the expression of D3 receptor mRNA and an increased accumulation of the alternatively-spliced, truncated D3-like mRNA, named D3nf D3nf mRNA is translated into a protein that participates in heteroligomeric assemblies with full-length D3-receptor protein. In contrast to monomeric and homoligomeric D3 proteins, the D3ID30f heteroligomers do not bind ligands with high affinity. Thus, both enhanced alternative splicing of D3-pre-mRNA and the heteroligomeric assembly of D3/D3nf proteins lead to a decreased expression of functional D3 receptors. This competing renewal seeks to extend our previous postmortem study on the relative expression of D3 and D3nf mRNAs in cortical regions of a new population of schizophrenic patients and their matched controls. Further studies use in vivo RNA splicing assays in conjunction with substrate D3 pre-mRNA to test the role of phospholipase C activity in the regulation of D3- and D3nf-specific splice-site selections. Additional studies use knockout mice to study functional consequences of D3 receptor inactivation. Our studies have shown that D3 receptor inactivation leads to a decreased expression of at least two genes that modulate neuronal activity (c-fos, calbindin) in anatomic structures critically involved in those cognitive processes that are vulnerable to disruption in schizophrenia. Thus, one series of anatomic and biochemical studies aims at elucidating mechanisms that lead to a decreased D1-receptor-mediated neocortical c-fos response in mice deficient for D3 and D2 receptors. Additional behavioral studies on these mutants further test whether this decreased D1-receptor activity has consequences for their performance in cognitive tasks. A final series of immunocytochemical experiments tests whether the expression of the striatal calcium-binding protein calbindin is decreased in D3 mutants because D3 receptor expression promotes calbindin expression in ventral striatal neurons that co-express D3 receptors and calbindin or because D3-receptors play a more general role in the postnatal development of the striatal calbindin-expressing system.