Background In Huntington disease (HD), the typical motor symptoms are associated with selective degeneration of striatal neurons. Importantly, non-motor aspects develop earlier and include changes in sleep and circadian rhythm, metabolic dysfunction and psychiatric symptoms. Recent studies point to selective vulnerability also of the lateral hypothalamic area (LHA) in HD, which may mediate several of the non-motor features of HD. Excitotoxicity, i.e. excessive glutamate signaling, has been linked to striatal degeneration in HD. Similar to the striatum, LHA receives glutamatergic synaptic inputs and excitotoxicity could thus be an important driving force in the development of LHA neuropathology.
Aims The aim of the study is to determine if excitotoxicity plays a role in the development of LHA neuropathology.
Methods Quantitative real time polymerase chain reaction (qRT-PCR) was used to assess mRNA levels of different components of the glutamate signaling machinery in the LHA of tissue dissected from the transgenic R6/2 and the BACHD mouse models as well as from mice expressing mutant huntingtin selectively in the hypothalamus using an adeno-associated viral vector approach. Vulnerability to exposure of intra-hypothalamic injections of the excitotoxin quinolinic acid was moreover evaluated in the same HD mouse models.
Results We detected changes in mRNA levels of several markers involved in glutamate signaling in the LHA. In our model of LHA excitotoxicity, we found that neurons expressing melanin concentrating hormone but not orexin were sensitive to excitotoxicity. Interestingly, orexin neurons in the R6/2 mouse model displays increased sensitivity to excitotoxicity.
Conclusions Excitotoxicity may play a role in the vulnerability of orexin neurons to the expression of mutant huntingtin in HD.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.