Dopamine control of striatal gene expression during development: relevanceto knockout mice for the dopamine transporter

The aim of this study was to determine at which developmental stage and how dopamine regulates the expression of striatal dopamine receptor and neurop eptide mRNAs. For this, we studied the expression of these mRNAs, in relati on to dopamine innervation, in normal mice from gestational day 13 (G13) to adult. Particularly, we investigated the adaptive changes in the expressio n of these markers in mice lacking the dopamine transporter during developm ent. We detected tyrosine hydroxylase, by immunohistochemistry, in the vent ral mesencephalon and the striatal anlage in both genotypes at G13, whereas the dopamine transporter appeared in the striatum of normal mice at G14. B y in situ hybridization, we detected striatal dopamine D1, D2, D3 receptor, and substance P mRNAs at G13, preproenkephalin A mRNA at G14 and dynorphin mRNA at G17 in normal mice. Although the time of initial detection and the distribution were not affected in mutant mice, quantitative changes were o bserved. Indeed, D1 and D2 receptor as well as preproenkephalin A mRNA leve ls were decreased from G14 on, and dynorphin mRNA level was increased from G17 on. In contrast, substance P mRNA level was unaffected. Our data demons trate that the influence of dopamine on striatal neurons occurs early durin g the development of the mesostriatal system as quantitative changes appear ed in mutant mice as soon as G14. These findings bring new insights to the critical influence of dopamine on the expression of striatal dopamine recep tor and neuropeptide mRNAs during development, and suggest that mesostriata l dopamine transmission functions from G14 on.