Abstract
Parkinson’s disease (PD) has been modeled in several animal species using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product 1-methyl-4-phenylpyridinium (MPP+). MPP+ selectively kills dopaminergic neurons in pars compacta of the substantia nigra, inducing parkinsonian symptoms in animals. Typically, neurotoxicity models of PD in zebrafish assess acute drug effects on locomotion. In the present study, we examined the lasting effects of MPP+ exposure and drug treatment in zebrafish larvae. Larvae were incubated in 500 μM MPP+, from 1 to 5 days post fertilization (dpf), followed by 24 h drug-free acclimation. At 6 dpf, the behavior was analyzed for locomotion, thigmotaxis, and sleep. Next, in separate assays we assessed the drug effects of brain injected glial cell-derived neurotrophic factor (GDNF) and 4-phenylbutyrate (PBA), co-incubated with MPP+. We show that MPP+ exposure consistently reduces swim distance, movement frequency, and cumulative time of movement; thus mimicking a parkinsonian phenotype of reduced movement. In contrast, MPP+ exposed larvae demonstrate reduced anxiety-like behavior and exhibit a sleep phenotype inconsistent with human PD: the larvae display longer sleep bouts, less sleep fragmentation, and more sleep. Previously reported rescuing effects of PBA were not replicated in this study. Moreover, whereas GDNF attenuated the sleep phenotype induced by MPP+, PBA augmented it. The current data suggest that MPP+ exposure generates a multifaceted phenotype in zebrafish and highlights that analyzing a narrow window of data can reveal effects that may be inconsistent with longer multi-parameter approaches. It further indicates that the model generally captures motor symptoms more faithfully than non-motor symptoms.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder with an estimated prevalence of 6.1 million individuals worldwide (Dorsey et al, 2018a)
Upon further evaluation of the cumulative time moving and duration of swim bouts, we show that MPP+ exposed zebrafish larvae spend less overall time moving compared to untreated larvae, but not due to shorter movement bouts
Due to the absence of a direct parkinsonian gait, balance, and posture in zebrafish larvae, a further breakdown of movement by evaluating cumulative movement time and duration of swim bouts can provide a valuable tool that allows for a comparison to motor symptoms of human PD
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder with an estimated prevalence of 6.1 million individuals worldwide (Dorsey et al, 2018a). PD is the fastest growing neurological disease (Dorsey et al, 2018b) and the cause of progressive detrimental motor and non-motor symptoms. Patients suffering from PD typically present one or more symptoms such as akinesia, MPP+ Model of Parkinson’s Revisited bradykinesia, tremors, and rigidity, induced by alterations in neuronal activity (Moustafa et al, 2016). PD is associated with non-motor symptoms such as autonomic dysfunction, psychiatric disorders, and sleep disorders (Aygun, 2018). Psychiatric disorders include anxiety, psychosis, apathy, impulse control disorder, Parkinson’s disease dementia, and depression (Han et al, 2018). Sleep disorders in PD are characterized as excessive daytime sleepiness, insomnia, fragmented sleep, or various REM movement disorders which can occur up to 10 years before the onset of motor symptoms (Pont-Sunyer et al, 2015)
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