title: Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease.
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 (Tfam) 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 littermates. 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.
authors.affiliation: Cellular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, U.S. Department of Health and Human Services, Baltimore, MD 21224, USA.
authors.forename: Cameron H
authors.initials: CH
authors.lastname: Good
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Hoffman
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Hoffer
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Chefer
authors.forename: Toni S
authors.initials: TS
authors.lastname: Shippenberg
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Bäckman
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
authors.forename: Lars
authors.initials: L
authors.lastname: Olson
authors.forename: Sandra
authors.initials: S
authors.lastname: Gellhaar
authors.forename: Dagmar
authors.initials: D
authors.lastname: Galter
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
mesh_terms: D000818:Animals; D003342:Corpus Striatum; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology*; D013378:Substantia Nigra; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D004298:Dopamine