Background Olfactory dysfunction and altered neurogenesis are observed in several neurodegenerative disorders including Huntington’s disease (HD). These deficits are an early symptom and correlate with decline in cognitive performance, depression and degeneration of olfactory regions in the brain.
Aims Despite clear evidence demonstrating olfactory dysfunction in HD patients, only limited details are available in murine models and the cause is unknown. Our goal is to determine if olfactory dysfunction is an early event in the pathogenesis of HD and to delineate the underlying mechanism(s).
Results We have previously shown decreased olfactory cortical volume in the YAC128 HD model. We now examined odour investigation behaviours and show that at 1 and 3 months YAC128 mice do not habituate to the odour as quickly in trial 2 (p < 0.05), and at 5 months the YAC128 mice investigate trial 1 odours longer than WT littermates (p < 0.05). Initial data also show an increase in GFAP and Iba-1 in the olfactory bulb (OB) in post-symptomatic YAC128 compared to WT. Furthermore, an increase in the active form of caspase-6 and caspase-8 are observed at 3 months in YAC128 OB vs WT. We also assessed the rat BACHD model. In the BACHD model, early increases in NeuN and atrophy of the OB (ANOVA p = 0.02) are observed. In addition, an increase in caspase-8 (ANOVA p = 0.02) expression at 6 months is observed vs. WT. Supporting this, we detect an increase in casp8 activation in the OB at 3 months of age.
Conclusions As we observe neuronal loss in the HD piriform cortex, a region that receives direct input from the OB and plays a role in odour discrimination and odour memory, this may reflect a loss in neuronal production or increased cell death in this area. The caspase activation studies support that cell death may be increased in both the murine HD piriform cortex and OB. However it cannot be ruled out that problems in neurogenesis are also occurring. Additional studies are required to ascertain the type and progression of olfactory dysfunction in the HD mice and highlight the specific olfactory pathway involved. Identification of early markers for HD will help inform therapeutic approaches and will clarify the utility of olfactory function tests in at risk HD individuals.
- mouse models