Mutant α-Synuclein Enhances Firing Frequencies in Dopamine Substantia Nigra Neurons by Oxidative Impairment of A-Type Potassium Channels
- Mahalakshmi Subramaniam1,
- Daniel Althof3,
- Suzana Gispert2,
- Jochen Schwenk3,
- Georg Auburger2,
- Akos Kulik3,4,
- Bernd Fakler3, and
- Jochen Roeper1
- 1Institute of Neurophysiology, Neuroscience Center,
- 2Department of Neurology, Goethe-University Frankfurt, 60590 Frankfurt, Germany, and
- 3Institute of Physiology II,
- 4BIOSS Centre for Biological Signaling Studies, University of Freiburg, D-79104 Freiburg, Germany
-
Author contributions: M.S., A.K., B.F., and J.R. designed research; M.S., D.A., J.S., and J.R. performed research; S.G. and G.A. contributed unpublished reagents/analytic tools; M.S., D.A., J.S., A.K., B.F., and J.R. analyzed data; M.S. and J.R. wrote the paper.
Abstract
Parkinson disease (PD) is an α-synucleinopathy resulting in the preferential loss of highly vulnerable dopamine (DA) substantia nigra (SN) neurons. Mutations (e.g., A53T) in the α-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 α-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 α-synuclein that might be useful as a novel biomarker for the “DA system at risk” before the onset of neurodegeneration in PD.
- Received December 3, 2013.
- Revision received August 18, 2014.
- Accepted August 19, 2014.
- Copyright © 2014 the authors 0270-6474/14/3413586-14$15.00/0
