Neurochemical, histological and behavioral profiling of the acute, sub-acute and chronic MPTP mouse model of Parkinson’s disease

Matteo Santoro* (Corresponding Author), Paola Fadda, Katie J. Clephan, Claire Hull, Peter Teismann, Bettina Platt, Gernot Riedel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Parkinson’s disease (PD) is a heterogeneous multi-systemic disorder unique to humans characterized by motor and non-motor symptoms. Preclinical experimental models of PD present limitations and inconsistent neurochemical, histological, and behavioral readouts. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD is the most common in-vivo screening platform for novel drug therapies; nonetheless, behavioral endpoints yielded amongst laboratories are often discordant and inconclusive. In this study, we characterized neurochemically, histologically, and behaviorally three different MPTP mouse models of PD to identify translational traits reminiscent of PD symptomatology. MPTP was intraperitoneally (i.p.) administered in three different regimens: i) acute - four injections of 20 mg/kg of MPTP every 2 hours; ii) sub-acute – one daily injection of 30 mg/kg of MPTP for 5 consecutive days; and iii) chronic – one daily injection of 4 mg/kg of MPTP for 28 consecutive days. A series of behavioral tests were conducted to assess motor and non-motor behavioral changes including anxiety, endurance, gait, motor deficits, cognitive impairment, circadian rhythm and food consumption. Impairments in balance and gait were confirmed in the chronic and acute models respectively, with the latter showing significant correlation with lesion size. The sub-acute model, by contrast, presented with generalized hyperactivity. Both, motor and non-motor changes were identified in the acute and sub-acute regime where habituation to a novel environment was significantly reduced. Moreover, we report increased water and food intake across all three models. Overall, the acute model displayed the most sever lesion size while across the three models striatal dopamine content (DA) did not correlate with behavioral performance. The present study demonstrates that detection of behavioral changes following MPTP exposure is challenging and does not correlate with the dopaminergic lesion extent.
Original languageEnglish
Pages (from-to)121-142
Number of pages22
JournalJournal of Neurochemistry
Volume164
Issue number2
Early online date3 Oct 2022
DOIs
Publication statusPublished - 1 Jan 2023

Bibliographical note

ACKNOWLEDGMENTS
We acknowledge the charity body “Tenovus Scotland” for financially supporting the project. A big thanks goes to the Aberdeen medical research facility for the great animal care and support provided during the conduct of MPPTP administration and animal behavioral testing. We also tanks the Wellcome Trust UK for having supported Katie J. Clephan with a summer vacation scholarship.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon request.

Keywords

  • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Behavioral Symptoms
  • DAT
  • dopamine transporter
  • Dopamine
  • Dopaminergic Neurons
  • enteric nervous system
  • Gait
  • HPLC
  • Movement Disorder
  • MPTP, Neostriatum
  • Neurochemistry
  • Neurotoxicity
  • Parkinson Disease
  • Parkinsonism
  • RRID
  • Research Resource Identifier (see scicrunch.org)
  • Substantia Nigra

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