Four male NSE M17 mice were crossed with eight wild-type female recipients of transplanted ovaries from R6/2 mice (Jackson Laboratories). Polymerase chain reaction was used for genotyping 8 . We used complete consecutive litters up to a certain birth date for symptomatic studies. Litters generated thereafter were used for the remaining studies. Mature IL-1β€ determination. Mature IL-1β€ quantification was done as previously described using an ELISA kit (Genzyme) 23 . Intracerebroventricular implantation of osmotic pumps. Spontaneously breathing seven-week-old R6/2 mice were anaesthetized, and a 2-cm sagittal incision was made over the skull. A small opening was made on the cranium 1 mm right lateral to the bregma. A microcannula was inserted to a depth of 3 mm, secured with a dental acrylic (Duralay, Bioanalytical Systems), and attached to an osmotic pump (Alzet). The pump was prefilled with 100 g per 20 g body weight of either zVAD-fmk or zFA-fmk (Enzyme Systems). The pumps continuously deliver the drug for four weeks. The experimenter was blinded to the identity of the drug used in the pump until the death of all the mice. In situ hybridization. We constructed oligonucleotide probes targeted against a human-specific intron of the human Huntington's disease transgene sequence (sequence 5Π-TCT GGG TTG CTG GGT CAC TCT GTC TCT GCG GAG CCG GGG G-3Π) and against the dopamine-D2-receptor gene (sequence 5Π-GGC AGG GTT GGC AAT GAT ACA CTC ATT CTG GTC TGTATT-3Π). Probes were 3Π-end labelled with 35 S-dATP using an oligonucleotide-labelling kit (NEN Life Science Products). Parasagittal sections (12 m) of frozen mouse brains were thaw-mounted onto poly-L-lysine-coated glass slides. Slides were fixed in 4% paraformaldehyde/0.1 M phosphate buffered-saline (PBS) for 10 min, washed in PBS for 3 Ο« 5 min, acetylated with 0.25% acetic anhydride in 0.1 M triethanolamine, pH 8.0, for 10 min, washed in PBS for 5 min, and dehydrated in graded ethanol solutions. Slides were incubated overnight at 37 ΠC with 80 l of hybridization buffer (50% formamide, 0.3 M NaCl, 10 mM Tris, 1 mM EDTA, 10% dextran sulphate, 1Γ Denhart's solution) containing radioactively labelled probe (30,000 c.p.m. per l). After hybridization, slides were washed in a series of sodium citrate-sodium chloride washes, rinsed with 70% ethanol and air-dried. The slides were apposed to β€-max film (Amersham) and exposed for 2 weeks before the film was developed. Film densities were analysed using a computer-based image-analysis system (M1, Imaging Research).Neuronal intranuclear inclusion and neurotransmitter receptor analysis.Receptor binding was done in parallel on fresh frozen brain tissue from wild-type, NSE M17Z, R6/2 and R6/2-NSE M17Z mice (n ΒΌ 4 animals per group) as described 5 . Immunohistochemistry wasperformedon12-m brain sections using antibodies against ubiquitin (Dako), glial fibrillary acidic protein or huntingtin 16 as described 17 . Western blotting was done according to standard techniques using an anti-huntingtin antibody (HF-1; courtesy of M. MacDonald).