Journal
JOURNAL OF NEUROSCIENCE
Volume 34, Issue 41, Pages 13586-13599Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5069-13.2014
Keywords
alpha-synuclein; A-type K channel; dopamine; in vivo; redox; substantia nigra
Categories
Funding
- BIOSS-2 [TP A6]
- [SFB 815]
- [SFB 1080]
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Parkinson disease (PD) is an alpha-synucleinopathy resulting in the preferential loss of highly vulnerable dopamine (DA) substantia nigra (SN) neurons. Mutations (e.g., A53T) in the alpha-synuclein gene (SNCA) are sufficient to cause PD, but the mechanism of their selective action on vulnerable DA SN neurons is unknown. In a mouse model overexpressing mutant alpha-synuclein (A53T-SNCA), we identified a SN-selective increase of in vivo firing frequencies in DA midbrain neurons, which was not observed in DA neurons in the ventral tegmental area. The selective and age-dependent gain-of-function phenotype of A53T-SCNA overexpressing DA SN neurons was in part mediated by an increase of their intrinsic pacemaker frequency caused by a redox-dependent impairment of A-type Kv4.3 potassium channels. This selective enhancement of stressful pacemaking of DA SN neurons in vivo defines a functional response to mutant alpha-synuclein that might be useful as a novel biomarker for the DA system at risk before the onset of neurodegeneration in PD.
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