Behavioral abnormalities precede neuropathological markers in rats transgenic for Huntington's disease

Abstract

Huntington's disease (HD) is caused by an expanded CAG repeat leading to the synthesis of an aberrant protein and to the formation of polyglutamine (polyQ)-containing inclusions and aggregates. Limited information is available concerning the association of neuropathological markers with the development of behavioral markers in HD. Using a previously generated transgenic rat model of HD (tgHD rat), we performed association studies on the time-course of behavioral symptoms (motor function, learning, anxiety) and the appearance of striatal atrophy, 1C2 immunopositive aggregates and polyQ recruitment sites, a precursor to these aggregates. At the age of 1 month, tgHD rats exhibited reduced anxiety and improved motor performance, while at 6 months motor impairments and at 9 months cognitive decline occurred. In contrast, polyQ recruitment sites appeared at around 6-9 months of age, indicating that HD-like behavioral markers preceded the appearance of currently detectable neuropathological markers. Interestingly, numerous punctate sites containing polyQ aggregates were also seen in areas receiving afferents from the densely recruiting regions suggesting either transport of recruitment-competent aggregates to terminal projections where initially 1C2 positive aggregates were formed or different internal properties of neurons in different regions. Furthermore, striatal atrophy was observed at the age of 12 months. Taken together, our findings support the hypothesis of a dynamic process leading to region- and age-specific polyQ recruitment and aggregation. The dissociation of onset between behavioral and neuropathological markers is suggestive of as yet undetected processes, which contribute to the early phenotype of these HD transgenic rats.

The Ventral Striatopallidum and Extended Amygdala in Huntington Disease

“…Histopathological hallmark is the accumulation of htt aggregates in affected brains (Difiglia et al, 1997;Gutekunst et al, 1999;Maat-Schiemann, 2007) which can be identified by immunohistochemistry with the so-called EM48, a widely used antibody which specifically detects N-terminal htt aggregates in brains of HD individuals and HD animal models Hodgson et al, 1999;Nguyen et al, 2006;von Hörsten et al, 2003). The role of htt aggregates and neurodegeneration is still controversial.…”

“…Among all Huntington animal models generated until now (and including the two extensively studied R6/2 and YAC128 mice), the tgHD rat is unique as it shows most prominent accumulation of htt aggregates in structures of the VSP and the EA (Niescery et al, 2009;Petrasch-Parwez et al, 2007). Moreover, it presents very early and ongoing emotional changes, which partly may be associated with dysfunctions of the VSP and EA (Bode et al, 2008;Faure et al, 2011;Nguyen et al, 2006). The distribution of htt accumulates in the medioventral striatum including the olfactory tubercle ( Fig.…”

Phenotyping of congenic dipeptidyl peptidase 4 (DP4) deficient Dark Agouti (DA) rats suggests involvement of DP4 in neuro-, endocrine, and immune functions

“…An Ugo Basile accelerating rotarod (model 7750) for rats, supplied by Technical & Scientific Equipment GmbH (TSE GmbH, Bad Homburg, Germany) was used, and training as well as experiments were conducted as described previously (12). For monitoring home cage activity, an infrared sensor controlled recording system (model No.…”

“…Shuttle box conditioning was used as a test of associative learning and was conducted using a TSE shuttle box system (TSE Systems GmbH) following the protocol as described previously (12). PPI of a startle response is the phenomenon in which a weak prepulse suppresses the response to a startling stimulus.…”

“…Furthermore, the mutation was confirmed by sequencing (data not shown). This strategy resulted in DP4 deficient animals, being comparable to CD26 knock-out mice (9), but providing the advantages of the species rattus norvegicus, being in metabolism, toxicology, and neurobiology more comparable to humans (10)(11)(12)(13). DP4 is ubiquitously expressed on leukocytes, epithelia, and endothelia of most vertebrate tissues and is involved in T-cell activation and cell adhesion processes as well as in the degradation of hormones, chemokines, and neuropeptides.…”