, 2001). R6/1 mice share most of the R6/2 pathology but at a later age. NIIs appear by 9 weeks (Naver et al., 2003), and R6/1 mice also show minimal gliosis (Yu et al., 2003) and similar dendritic spine atrophy check details by 8 months (Spires et al., 2004). Apoptotic and necrotic cells are rarely seen in the striatum of R6/2 and R6/1 mice, despite significant atrophy and ventricular enlargement; instead, electron micrographs contain so-called dark neurons, displaying condensation of the cytoplasm and nucleus without the chromatin fragmentation and nuclear blebbing characteristic of apoptosis (Yu et al., 2003). In contrast, 3-month-old N171-82Q mice do demonstrate cortical and

striatal apoptotic neurons, with reactive gliosis by 4 months. Note that in old (22–30 week) R6/2 chimeras, gliosis is apparent in regions densely populated in transgenic neurons (Reiner et al., 2007), and particularly old R6/2 animals (17 weeks) show astrocytes with processes enveloping degenerating neurons (Turmaine et al., 2000). Therefore, the signals necessary to develop gliosis in R6/2 mice may be present, but the mice may die before glial recruitment and activation. N171-82Q mice also presented with striatal

degeneration and ventricular enlargement by 17 weeks (Gardian CHIR-99021 supplier et al., 2005) and NIIs in many brain regions (cortex, hippocampus, cerebellum, and striatum among others) by late endstage of 6.5 months. NIIs are not seen until far after symptom onset in full-length transgenic HD lines. YAC128 mice display behavioral symptoms at 12 months, and striatal neuron loss of ∼15% is seen by this time (Slow et al., 2003) along with increased intranuclear HTT staining of

certain brain structures (Van Raamsdonk et al., 2005a). However, NIIs did not show up until 18 months of age and only populated ∼30% of striatal neurons and ∼5% of cortical neurons. NIIs were absent in the YAC128 hippocampus, a site of NII staining in endstage R6/2′s (Morton et al., 2000). In the other distinct full-length transgenic strain, BACHD mice also mafosfamide display atrophy of the cortex and striatum by as much as 30% at 12 months (Gray et al., 2008), with 14% of striatal neurons with the aforementioned dark morphology. Interestingly and as opposed to R6 mice, inclusions (over 90%) were extranuclear and were more common in the cortex than striatum, a feature reminiscent of adult onset HD. R6/2 chimaeras suggest that inclusions themselves may be neither toxic nor markers of cells about to die, and a strain arising with a spontaneous mutation in the YAC128 transgene [termed Shortstop (Ss) for its early termination] provides further evidence to this end (Slow et al., 2005). The mutation truncated the transgene after exon 2, providing a product with 128 glutamines and an expected and observed protein size similar to that encoded by the R6/2 transgene.