Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model

Stephanie Janezic, Sarah Threlfell, Paul D. Dodson, Megan J. Dowie, Tonya N. Taylor, Dawid Potgieter, Laura Parkkinen, Steven L. Senior, Sabina Anwar, Brent Ryan, Thierry Deltheil, Polina Kosillo, Milena Cioroch, Katharina Wagner, Olaf Ansorge, David M. Bannerman, J. Paul Bolam, Peter J. Magill, Stephanie J. Cragg, Richard Wade-Martins*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

171 Citations (Scopus)

Abstract

The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA-OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA-OVXmice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCAOVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA-OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number42
DOIs
Publication statusPublished - 15 Oct 2013

Keywords

  • Behavioral phenotyping
  • Dopamine transmission
  • In vivo electrophysiology
  • Neurodegeneration
  • Voltammetry

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