Dopaminergic neurons exhibit an age-dependent decline in electrophysiological parameters in the MitoPark mouse model of Parkinson’s disease

Sarah Y. Branch, Cang Chen, Ramaswamy Sharma, James D. Lechleiter, Senlin Li, Michael J. Beckstead

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Dopaminergic neurons of the substantia nigra (SN) play a vital role in everyday tasks, such as reward-related behavior and voluntary movement, and excessive loss of these neurons is a primary hallmark of Parkinson’s disease (PD). Mitochondrial dysfunction has long been implicated in PD and many animal models induce parkinsonian features by disrupting mitochondrial function. MitoPark mice are a recently developed genetic model of PD that lacks the gene for mitochondrial transcription factor A specifically in dopaminergic neurons. This model mimics many distinct characteristics of PD including progressive and selective loss of SN dopamine neurons, motor deficits that are improved by L-DOPA, and development of inclusion bodies. Here, we used brain slice electrophysiology to construct a timeline of functional decline in SN dopaminergic neurons from MitoPark mice. Dopaminergic neurons from MitoPark mice exhibited decreased cell capacitance and increased input resistance that became more severe with age. Pacemaker firing regularity was disrupted in MitoPark mice and ion channel conductances associated with firing were decreased. Additionally, dopaminergic neurons from MitoPark mice showed a progressive decrease of endogenous dopamine levels, decreased dopamine release, and smaller D2 dopamine receptor-mediated outward currents. Interestingly, expression of ion channel subunits associated with impulse activity (Cav1.2, Cav1.3, HCN1, Nav1.2, and NavB3) was upregulated in older MitoPark mice. The results describe alterations in intrinsic and synaptic properties of dopaminergic neurons in MitoPark mice occurring at ages both before and concurrent with motor impairment. These findings may help inform future investigations into treatment targets for prodromal PD.

Original languageEnglish (US)
Pages (from-to)4026-4037
Number of pages12
JournalJournal of Neuroscience
Volume36
Issue number14
DOIs
StatePublished - Apr 6 2016

Keywords

  • Dopamine
  • Electrophysiology
  • Mice
  • MitoPark
  • Neurotransmission
  • Parkinson’s

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint

Dive into the research topics of 'Dopaminergic neurons exhibit an age-dependent decline in electrophysiological parameters in the MitoPark mouse model of Parkinson’s disease'. Together they form a unique fingerprint.

Cite this