Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease
Open Access
- 13 January 2011
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 25 (4), 1333-1344
- https://doi.org/10.1096/fj.10-173625
Abstract
Parkinson's disease (PD) involves progressive loss of nigrostriatal dopamine (DA) neurons over an extended period of time. Mitochondrial damage may lead to PD, and neurotoxins affecting mitochondria are widely used to produce degeneration of the nigrostriatal circuitry. Deletion of the mitochondrial transcription factor A gene (Tfαm) in C57BL6 mouse DA neurons leads to a slowly progressing parkinsonian phenotype in which motor impairment is first observed at ˜12 wk of age. L-DOPA treatment improves motor dysfunction in these “MitoPark” mice, but this declines when DA neuron loss is more complete. To investigate early neurobiological events potentially contributing to PD, we compared the neurochemical and electrophysiological properties of the nigrostriatal circuit in behaviorally asymptomatic 6- to 8-wk-old MitoPark mice and age-matched control litter-mates. Release, but not uptake of DA, was impaired in MitoPark mouse striatal brain slices, and nigral DA neurons lacked characteristic pacemaker activity compared with control mice. Also, hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel function was reduced in MitoPark DA neurons, although HCN messenger RNA was unchanged. This study demonstrates altered nigrostriatal function that precedes behavioral parkinsonian symptoms in this genetic PD model. A full understanding of these presymptomatic cellular properties may lead to more effective early treatments of PD.—Good, C. H., Hoffman, A. F., Hoffer, B. J., Chefer, V. I., Shippenberg, T. S., Backman, C. M., Larsson, N.-G., Olson, L., Gellhaar, S., Galter, D., Lupica, C. R. Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease. FASEB J. 25, 1333–1344 (2011). www.fasebj.orgKeywords
Funding Information
- National Institutes of Health
- National Institute on Drug Abuse
- Vetenskapsrådet
- Hjärnfonden
- Bertil Hållstens Forskningsstiftelse
- ParkinsonFörbundet
- Swedish Brain Power
- Michael J. Fox Foundation for Parkinson's Research
- Karolinska Institutet
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