Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington's disease.

Transgenic R6/1 mice incorporate a human genomic fragment containing promoter elements exon 1 and a portion of intron 2 of the Huntingtin gene responsible for Huntington's disease. They develop late-onset neurological deficits in a manner similar to the motor abnormalities of the disorder. As essential fatty acids are phospholipid components of cell membranes which may influence cell death and movement disorder phenotype, R6/1 and normal mice were randomised to receive a mixture of essential fatty acids or placebo on alternate days throughout life. Over mid-adulthood, topographical assessment of behaviour revealed R6/1 transgenics to evidence progressive shortening of stride length, with progressive reductions in locomotion, elements of rearing, sniffing, sifting and chewing, and an increase in grooming. These deficits were either not evident or materially diminished in R6/1 transgenics receiving essential fatty acids. R6/1 transgenics also showed reductions in body weight and in brain dopamine D(1)-like and D(2)-like quantitative receptor autoradiography which were unaltered by essential fatty acids.These findings indicate that early and sustained treatment with essential fatty acids are able to protect against motor deficits in R6/1 transgenic mice expressing exon 1 and a portion of intron 2 of the Huntingtin gene, and suggest that essential fatty acids may have therapeutic potential in Huntington's disease.

Early direct and transneuronal effects in mice with targeted expression of a toxin gene to D1 dopamine receptor neurons.

The neurochemical profile was examined at postnatal day 3-4 in mutant mice generated by in vivo Cre mediated activation of an attenuated diphtheria toxin gene inserted into the D1 dopamine receptor gene locus. An earlier study of this model had shown that D1 dopamine receptor, substance P and dynorphin were not expressed in the striatum. Quantitative in situ hybridization analysis showed an increase in D2 dopamine receptor and enkephalin messenger RNA expression. The nigrostriatal pathway in the mutant pups was intact with a normal number of dopaminergic neurons in the substantia nigra and the ventral tegmental area in addition to a normal pattern of striatal dopamine transporter and tyrosine hydroxylase immunoreactivity. Quantitative analysis of striatal dopamine transporter density using [3H]mazindol showed a reduction of 26% suggesting a degree of transneuronal down-regulation. There was also a 49% reduction of striatal GABA receptor binding and a 36% reduction of striatal muscarinic receptor binding in mutant pups. The number of healthy striatal neuropeptide Y-containing interneurons was also substantially down-regulated in the mutant striatum. In contrast, there was an increase in the number of striatal cholinergic interneurons. Down-regulated cortical GABA receptor and muscarinic receptor binding was also observed in addition to subtle morphological changes in the neuropeptide Y-expressing population of cortical neurons. The changes reflect the early cascade of events which follows the ablation of D1 dopamine receptor-positive cells. Although extensive changes in a number of striatal and cortical neurons were demonstrated, only subtle transneuronal effects were seen in the nigrostriatal pathway.

Targeted expression of a toxin gene to D1 dopamine receptor neurons by cre-mediated site-specific recombination.

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.