Background Metabolic and psychiatric disturbances occur early on in the clinical manifestation of Huntington's disease (HD). The hypothalamus has emerged as an important site of pathology and alterations in this area and its neuroendocrine circuits may play a role in causing early non-motor symptoms and signs in HD. Leptin is a hormone that controls energy homeostasis by signalling through leptin receptors in the hypothalamus. Disturbed leptin action is implicated in both obesity and depression and altered circulating levels of leptin have been reported in both clinical HD and rodent models of the disease. Pathological leptin signalling may therefore be involved in causing the metabolic and psychiatric disturbances of HD.
Aim To investigate the impact of inactivation of mutant huntingtin (htt) in leptin receptor-expressing neurons on the metabolic and psychiatric phenotype of the BACHD mouse model.
Methods In order to selectively inactivate mutant htt in leptin receptor expressing neurons BACHD mice were bred with mice expressing cre-recombinase after the leptin receptor gene (B6.129-Leprtm2(cre)Rck/J). Offsprings from the F1 generation were assessed for body weight at 2 and 6 months and percentage body fat (using dual energy x-ray absorptiometry) at 6 months. Depressive- and anxiety-like behaviours were evaluated at 6 months with the Porsolt forced-Swim Test and the Elevated Plus Maze, respectively.
Results Inactivation of mutant htt in leptin receptor-expressing neurons in the BACHD mouse does not have an effect on the metabolic phenotype or anxiety-like behaviour. For depressive-like behaviour, all genotypes showed high immobility in the Porsolt forced-Swim Test. This was likely due to a strain effect and therefore it was difficult to assess the effect of mutant htt in LepR neurons on depressive-like behaviour.
Conclusion This data suggests that mutant htt disrupts critical hypothalamic pathways by mechanisms other than interference with intracellular leptin signalling.
- leptin receptor
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