Objective: To investigate the phenotype of noradrenergic (NA) neurons in an animal model with selective overexpression of α-synuclein (αSyn) in the locus coeruleus (LC) with histological, physiological and behavioral methods.

Background: Viral vector-based focal overexpression of αSyn is a versatile method for modeling certain aspects of Parkinson’s disease (PD) such as the development of synucleinopathy and neuronal loss. Here we propose to explore the understudied role of the LC in an unprecedented targeted approach in mice. According to Braak staging of PD, the LC is one of the first brain regions affected by Lewy pathology. Notably, the LC is the main source of NA projections and it has many circuit links that are associated with clinical phenotypes of prodromal stages of PD.

Method: We designed a tyrosine hydroxylase (TH) promoter controlled recombinant adeno-associated virus (AAV) 2/5 vector carrying human-wildtype αSyn. A total of 60 animals underwent stereotactic operation targeting the right LC. Histology and whole-cell patch-clamp recording were performed at 9 weeks of αSyn overexpression followed by ongoing long-term evaluation at 24 weeks. The degree of the αSyn burden in selective regions of interest was quantified at 9 and 24 weeks. Motor and non-motor related behavioral assays were also employed.

Results: We report over 98% of the viral transduction rate specifically in the LC neurons. Mild loss of TH+ neurons in the LC was found and markers of αSyn-aggregation (αSyn phosphorylated at Serine 129 and Ubi1) and of gliosis were observed in the LC at 24 weeks. Interestingly, the αSyn overexpressed LC neurons revealed similar pacemaking activity of frequency and after-hyperpolarization amplitude at 9 weeks compared to the control. The whole-brain analysis showed αSyn propagation to distinctive LC-output regions, including the amygdala and the bed nucleus of the stria terminalis (BNST). In addition, motor test results demonstrated no significant alteration in locomotion and gait behaviors in αSyn groups, whereas the results of the non-motor related tasks (gastrointestinal dysfunction and hyposmia) will next be analyzed.

Conclusion: We will present histological, electrophysiological and behavioral data at 9 and 24 weeks in a new mouse model with selective αSyn overexpression in the LC neurons. We will discuss the advantages and limitations of this model for prodromal PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/selective-%ce%b1-synuclein-overexpression-induced-pathology-in-noradrenergic-neurons-a-new-mouse-model-for-prodromal-parkinsons-disease/