A TRANSGENIC MOUSE MODEL TO STUDY TRANSSYNAPTIC REGULATION OF TYROSINE-HYDROXYLASE GENE-EXPRESSION

Previous studies demonstrated that 9 kb of the rat tyrosine hydroxylas e (TH) 5' flanking sequence directed appropriate spatiotemporal expres sion of a lacZ reporter gene to catecholaminergic cells in the CNS of transgenic mice, In the present study, specificity of transgene expres sion was further extended to demonstrate cell type-specific functional regulation of lacZ expression using manipulations known to alter endo genous TH expression. Alterations in lacZ reporter expression should p arallel changes in endogenous TH levels if the DNA elements mediating these functional changes of TH expression in vivo reside within the 9 kb of the TH promoter region. Naris closure induced an activity-depend ent decrease of TH expression in dopaminergic periglomerular cells in the olfactory bulb that was paralleled by down-regulation of lacZ expr ession in the transgenic mice. Densitometry and image analysis were us ed to quantify lacZ expression following acute reserpine administratio n (5 mg/kg, s.c.), which up-regulates endogenous TH. At 48 h postinjec tion, analysis of OD values indicated a significant increase of X-gal staining in the locus coeruleus and ventral tegmental area but not in the substantia nigra or olfactory bulb of reserpine-treated transgenic animals. These data showed that the 9-kb sequence also mediates cell type-specific transsynaptic regulation of reporter gene expression. An alysis of this transgenic animal offers a useful model system to study in vivo regulation of TH gene expression.