ENHANCED CLEAVAGE OF AN ATYPICAL INTRON OF DOPAMINE D-3-RECEPTOR PRE-MESSENGER-RNA IN CHRONIC-SCHIZOPHRENIA

The D-2-class of dopamine receptors (D-2, D-3, and D-4) is a target fo r typical and atypical neuroleptic drugs. They have been considered, t herefore, as factors that may contribute to the pathophysiology of psy chotic disorders. Interestingly, in cortical brain tissues obtained po stmortem form patients with chronic schizophrenia D-3 mRNA was found t o be significantly lower than in the corresponding anatomic regions of controls. Because the expression of a truncated D-3-like mRNA (named D-3nf) appeared to be unaffected in schizophrenic brains, these findin gs suggest the possibility that the loss of D-3 mRNA results from an a bnormal splicing of D-3 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 D-3 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 splic eosomal intron in D-3 pre-mRNA that has a noncanonical 3' splice site. (2) Substrate D-3 pre-mRNA was spliced in vivo in stably transfected rat GH3 cells. Despite the atypical 3' cleavage that is necessary to g enerate D-3nf mRNA, D-3 and D-3nf mRNA were found to be processed at s imilar amounts. (3) The relative D-3/D-3nf splicing efficiencies were then determined in the anterior cingulate cortex of postmortem brains obtained from controls and from patients with chronic schizophrenia. S ignificant differences were found between the relative levels of D-3 a nd D-3nf mRNA, suggesting that an enhanced D-3nf-specific splicing of D-3 pre-mRNA in schizophrenia leads to a decreased expression of D-3 m RNA.