Objective: To determine the longitudinal effects of synucleinopathy and synucleinopathy-triggered nigrostriatal degeneration on basal and evoked striatal dopamine (DA) release in the striatum at 4 and 6 months after striatal introduction of alpha-synuclein (a-syn) pre-formed fibrils (PFFs).

Background: Accumulation of a-syn inclusions (Lewy bodies) is a pathological hallmark of Parkinson’s disease (PD) and has the potential to disrupt DA neurotransmission and contribute to DA neuron death in the substantia nigra [1]. The PFF rat model replicates many of the changes seen during the progression of PD [2], however, when DA release dysfunction emerges remains an unanswered and critical question we sought to address.

Method: Adult Sprague-Dawley rats (n=10/group) received a unilateral infusion of either mouse a-syn PFFs or saline at 2 striatal sites. In a between subjects design, at either 4 or 6 months post-infusion, rats underwent in vivo microdialysis of the striatum. On test days, artificial cerebral spinal fluid was perfused for 60 min after which 6, 20 min samples were taken for baseline extracellular DA levels. At 170 min, DA release was then stimulated by increasing the potassium in the perfusate for 20 min [3]. At 290 min rats received L-DOPA to examine effects of PFF on L-DOPA induced DA release. Dialysate samples were analyzed by HPLC and motor deficits were assayed by the forepaw adjusting steps test the day before microdialysis testing [4].

Results: Results suggest that at 4 months, the motor phenotype is undetectable while an emerging reduction in nigral tyrosine hydroxylase immunoreactive neurons is observed at 4 months with a significant decline at 6 months [2]. Our evidence additionally suggests that at 4 and 6 months, escalating reductions in DA levels, DA metabolites and extracellular DA will be significant [5].

Conclusion: The PFF model produces robust and reproducible synucleinopathy with burgeoning DA neuron loss. A-syn aggregates also seem to modify striatal DA transmission that our data suggest emerges at 4 months and intensifies at 6 months. Collectively our work implicates an important time window in the PFF model where novel disease-modifying therapies may be identified and tested.

References: References: 1. Bridi & Hirth, 2018 PMID: 29515354 2. Patterson et. al., 2019 PMID: 31276792 3. Cass et. al., 2014 PMID: 24858239 4. Bhide et. al., 2015 PMID: 25866285 5. Paumier et. al., 2015 PMID: 26093169

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterization-of-striatal-dopaminergic-neurotransmission-in-the-rat-pre-formed-fibril-models-of-parkinsons-disease/