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Volume 16, Number 24, Issue of December 15, 1996 pp. 7902-7909
Copyright ©1996 Society for Neuroscience

Enhanced Cleavage of an Atypical Intron of Dopamine D₃-Receptor Pre-mRNA in Chronic Schizophrenia

Received Aug. 12, 1996; revised Sept. 20, 1996; accepted Oct. 1, 1996.

Claudia Schmauss

Department of Psychiatry and Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029

The D₂-class of dopamine receptors (D₂, D₃, and D₄) is a target for typical and atypical neuroleptic drugs. They have been considered, therefore, as factors that may contribute to the pathophysiology of psychotic disorders. Interestingly, in cortical brain tissues obtained postmortem form patients with chronic schizophrenia D₃ mRNA was found to be significantly lower than in the corresponding anatomic regions of controls. Because the expression of a truncated D₃-like mRNA (named D_3nf) appeared to be unaffected in schizophrenic brains, these findings suggest the possibility that the loss of D₃ mRNA results from an abnormal splicing of D₃ pre-mRNA in schizophrenia that is accompanied by an increased accumulation of the truncated D_3nf mRNA. To test this, three approaches were taken. (1) Substrate D₃ pre-mRNA was spliced in vitro in HeLa nuclear extracts. Results from these experiments show that D_3nf mRNA results from the alternative removal of a short spliceosomal intron in D₃ pre-mRNA that has a noncanonical 3 splice site. (2) Substrate D₃ pre-mRNA was spliced in vivo in stably transfected rat GH3 cells. Despite the atypical 3 cleavage that is necessary to generate D_3nf mRNA, D₃ and D_3nf mRNA were found to be processed at similar amounts. (3) The relative D₃/D_3nf splicing efficiencies were then determined in the anterior cingulate cortex of postmortem brains obtained from controls and from patients with chronic schizophrenia. Significant differences were found between the relative levels of D₃ and D_3nf mRNA, suggesting that an enhanced D_3nf-specific splicing of D₃ pre-mRNA in schizophrenia leads to a decreased expression of D₃ mRNA.

Key words: D₃ pre-mRNA; in vitro splicing; in vivo splicing; primer extension; S1 nuclease protection; postmortem brain RNA

This article has been cited by other articles:

				B. Mitterauer Nonfunctional Glial Proteins in Tripartite Synapses: A Pathophysiological Model of Schizophrenia Neuroscientist, June 1, 2005; 11(3): 192 - 198. [Abstract] [PDF]

				R. D. Catalano, T. Kyriakou, J. Chen, A. Easton, and E. W. Hillhouse Regulation of Corticotropin-Releasing Hormone Type 2 Receptors by Multiple Promoters and Alternative Splicing: Identification of Multiple Splice Variants Mol. Endocrinol., March 1, 2003; 17(3): 395 - 410. [Abstract] [Full Text] [PDF]

				C. Schmauss Dopamine Receptors: Novel Insights from Biochemical and Genetic Studies Neuroscientist, April 1, 2000; 6(2): 127 - 138. [Abstract] [PDF]

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