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The Journal of Neuroscience, December 1, 1998, 18(23):9845-9857

Targeted Expression of a Toxin Gene to D1 Dopamine Receptor Neurons by Cre-Mediated Site-Specific Recombination

John Drago¹, Poolpol Padungchaichot¹, John Y. F. Wong¹, Andrew J. Lawrence², Julie F. McManus¹, Sony H. Sumarsono⁴, Anthony L. Natoli¹, Merja Lakso⁵, Nigel Wreford³, Heiner Westphal⁶, Ismail Kola⁴, and David I. Finkelstein¹

¹ Neurosciences Group, Department of Anatomy, ² Department of Pharmacology, ³ Department of Anatomy, and ⁴ Molecular Genetics and Development Group, Institute of Reproduction and Development, Monash University, Clayton, Victoria, 3168, Australia, ⁵ A. I. Virtanen Institute, BioTeknia, Neulaniementie 2, 70210 Kuopio, Finland, and ⁶ Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-2790

Idiopathic Parkinson's disease involves the loss of midbrain dopaminergic neurons, resulting in the presynaptic breakdown of dopaminergic transmission in the striatum. Huntington's disease and some neurodegenerative diseases with Parkinsonian features have postsynaptic defects caused by striatal cell death. Mice were generated in which an attenuated form of the diphtheria toxin gene (tox-176) was expressed exclusively in D1 dopamine receptor (D1R)-positive cells with the aim of determining the effect of this mutation on development of the basal ganglia and on the locomotor phenotype. Transgenic mice expressing Cre, a site-specific DNA recombinase, were crossed with a second line in which a transcriptionally silenced tox-176 gene was inserted into the D1R gene locus by homologous recombination. Young doubly transgenic mutant mice expressing the tox-176 gene displayed bradykinesia, dystonia, and had falls caused by myoclonic jerks. The mutant brain had evidence of apoptosis and reactive gliosis and, consistent with the D1R expression pattern, the striatum was reduced in volume, and the Islands of Calleja were absent. In contrast, the cortex was of normal thickness. D1Rs were not detectable in mutants by in situ hybridization or ligand autoradiography, whereas D2 dopamine receptor (D2R) mRNA and protein was present in the striatum. In addition, substance P and dynorphin, neuropeptides known to be expressed in D1R-positive striatonigral projection neurons were not detectable. Enkephalin, a marker found in D2-positive striatopallidal projection neurons was expressed in the mutant brain. The mutant represents a novel neurodegenerative disease model with a dramatic extrapyramidal phenotype.

Key words: D1 dopamine receptor; basal ganglia; Cre recombinase; gene targeting; striatum; Parkinson's disease

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18239845-13$05.00/0

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