Cellular localization and development of neuronal intranuclear inclusions in striatal and cortical neurons in R6/2 transgenic mice

Abstract

The cellular localization and development of neuronal intranuclear inclusions (NIIs) in cortex and striatum of R6/2 HD transgenic mice were studied to ascertain the relationship of NIIs to symptom formation in these mice and gain clues regarding the possible relationship of NII formation to neuropathology in Huntington's disease (HD). All NIIs observed in R6/2 mice were ubiquitinated, and no evidence was observed for a contribution to them from wild-type huntingtin; they were first observed in cortex and striatum at 3.5 weeks of age. In cortex, NIIs increased rapidly in size and prevalence after their appearance. Generally, cortical projection neurons developed NIIs more rapidly than cortical interneurons containing calbindin or parvalbumin. Few cortical somatostatinergic interneurons, however, formed NIIs. In striatum, calbindinergic projection neurons and parvalbuminergic interneurons rapidly formed NIIs, but they formed more gradually in cholinergic interneurons, and few somatostatinergic interneurons developed NIIs. Striatal NIIs tended to be smaller than those in cortex. The early accumulation of NIIs in cortex and striatum in R6/2 mice is consistent with the early appearance of motor and learning abnormalities in these mice, and the eventual pervasiveness of NIIs at ages at which severe abnormalities are evident is consistent with their contribution to a neuronal dysfunction underlying the abnormalities. That cortex develops larger NIIs than striatum, however, is inconsistent with the preferential loss of striatal neurons in HD but is consistent with recent evidence of early morphological abnormalities in cortical neurons in HD. That calbindinergic and parvalbuminergic striatal neurons develop large NIIs is consistent with a contribution of nuclear aggregate formation to their high degree of vulnerability in HD.

The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies

“…For example, in the R6/2 striatum around 98% of the striatal projection neurons (calbindin positive) exhibit huntingtin inclusions at 15 weeks of age, whereas there are only few inclusions (1-2%) in certain neuronal types, such as somatostatin containing neurons. 31 Within the striatum, it appears that interneurons, in contrast to the efferent projection neurons, display fewer inclusions. 31,32 The inclusions are ubiquitinated, and the 20S subunit of the proteasome is recruited into the aggregates in R6/1 mice.…”

“…31 Within the striatum, it appears that interneurons, in contrast to the efferent projection neurons, display fewer inclusions. 31,32 The inclusions are ubiquitinated, and the 20S subunit of the proteasome is recruited into the aggregates in R6/1 mice. 33 Despite so few neurons actually dying in the brains of R6 mice, there is ample evidence that their brains do not function in a normal manner.…”

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…However, unlike the expression of the dominantnegative caspase-1 transgene (Ona et al, 1999), minocyclinemediated inhibition of caspase-1 did not affect NIIs formation (Chen et al, 2000). Since NIIs can be first detected in the cortex and striatum as early as 3.5 weeks (Meade et al, 2002), the fact that minocycline treatment was started at 6 weeks of age (when NIIs are already widely distributed throughout the brain), may account for this lack of effect. Minocycline was efficient in reducing the activities of caspase-1 and the inducible isoform of nitric oxide synthase (iNOS) and decreasing the up-regulation of caspases 1 and 3 expression in R6/2 brains.…”

Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis

“…On a molecular level, intraneuronal inclusions that contain an amino-terminal fragment of mutant htt have been identified in the brains of both human HD patients and HD animal models (DiFiglia et al, 1997;Ho et al, 2001). Inclusion formation does not directly correlate with increased neuronal vulnerability, as striatal neurons have been shown to form fewer inclusions than cortical neurons (Meade et al, 2002). However, within the striatum, vulnerable neuronal subtypes do form more inclusions than unaffected neuronal subtypes, and they do so at an earlier age (Meade et al, 2002).…”

“…Inclusion formation does not directly correlate with increased neuronal vulnerability, as striatal neurons have been shown to form fewer inclusions than cortical neurons (Meade et al, 2002). However, within the striatum, vulnerable neuronal subtypes do form more inclusions than unaffected neuronal subtypes, and they do so at an earlier age (Meade et al, 2002). The consequences of inclusion formation have been unclear, with earlier reports suggesting a pathological function of inclusions in HD progression (Hackam et al, 1999).…”