Journal
BEHAVIOURAL BRAIN RESEARCH
Volume 333, Issue -, Pages 150-160Publisher
ELSEVIER
DOI: 10.1016/j.bbr.2017.06.047
Keywords
Intracerebroventricular (i.c.v.) infusion; Olfactory dysfunction; Anxiety-like behavior; Olfactory bulb; Dopamine; Tyrosine hydroxylase; Parkinson's disease
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Funding
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
- National Institute for Translational Neuroscience (INNT)
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Parkinson's disease (PD) is characterized by motor dysfunction, which is preceded by a number of non-motor symptoms including olfactory deficits. Aggregation of alpha-synuclein (alpha-syn) gives rise to Lewy bodies in dopaminergic neurons and is thought to play a central role in PD pathology. However, whether amyloid fibrils or soluble oligomers of alpha-syn are the main neurotoxic species in PD remains controversial. Here, we performed a single intracerebroventricular (i.c.v.) infusion of a-syn oligomers (alpha-SYOs) in mice and evaluated motor and non-motor symptoms. Familiar bedding and vanillin essence discrimination tasks showed that alpha-SYOs impaired olfactory performance of mice, and decreased TH and dopamine levels in the olfactory bulb early after infusion. The olfactory deficit persisted until 45 days post-infusion (dpi). alpha-SYO-infused mice behaved normally in the object recognition and forced swim tests, but showed increased anxiety-like behavior in the open field and elevated plus maze tests 20 dpi. Finally, administration of alpha-SYOs induced late motor impairment in the pole test and rotarod paradigms, along with reduced TH and dopamine content in the caudate putamen, 45 dpi. Reduced number of TH-positive cells was also seen in the substantii nigra of alpha-SYO-injected mice compared to control. In conclusion, i.c.v. infusion of alpha-SYOs recapitulated some of PD-associated non-motor symptoms, such as increased anxiety and olfactory dysfunction, but failed to recapitulate memory impairment and depressive-like behavior typical of the disease. Moreover, alpha-SY0s i.c.v. administration induced motor deficits and loss of TH and dopamine levels, key features of PD. Results point to alpha-syn oligomers as the proximal neurotoxins responsible for early non-motor and motor deficits in PD and suggest that the i.c.v. infusion model characterized here may comprise a useful tool for identification of PD novel therapeutic targets and drug screening.
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