Background Huntington's disease (HD) is characterised by motor symptoms, cognitive decline and psychiatric disturbances. The neuropathology is widespread but the striatum and the cerebral cortex are among the most severely affected areas. As mutant huntingtin (htt) is ubiquitously expressed, it has been difficult to establish structure-to-function relationships for the development of the different clinical manifestations.
Aims Our aim was to develop a new rat model of HD with targeted forebrain expression of htt.
Methods We have injected recombinant adeno-associated viral vectors of serotype 5 (rAAV5) expressing an 853 amino acid fragment of either wildtype (htt853-18Q) or mutant (htt853-79Q) htt, or green fluorescent protein (GFP) in the dorsal striatum of neonatal rats. Adult rats were assessed for neuropathology, body weight, anxiety–like behaviour and motor activity at 2 and 6 months post-injection.
Results/Outcomes Neuropathological assessment at 6 months showed long-term expression of GFP in the cerebral cortex and the dorsal striatum. In htt853-79Q injected brains we found ubiquitinated htt inclusions mainly in the cortical region. No gliosis or microglia activation was detected and stereological quantifications of NeuN- and DARPP-32 positive cells revealed no cell loss after expression of htt853-79Q. Interestingly, the same vector injected into the hypothalamus led to rapid formation of htt inclusions and orexin loss. No differences in the general motor activity or body weight were observed after targeted forebrain expression of the mutant htt fragment. However, overexpression of htt853-18Q led to significantly less anxiety-like behaviour.
Conclusions This AAV-vector mediated model of HD demonstrated widespread forebrain expression of mutant htt and could be an interesting tool to investigate specific effects of htt in different brain regions.
- gene transfer