Striatal neuroadaptation and rescue of locomotor deficit by L-dopa in aphakia mice, a model of Parkinson's disease.
Preferential neurodegeneration of dopaminergic neurons in the ventral substantia nigra of the midbrain is a hallmark of Parkinson's disease. The homeobox transcription factor Pitx3 is similarly and selectively expressed in the same neurons. Pitx3 deficiency in a natural mouse mutant, the aphakia mouse, was correlated with the loss of these neurons and with a deficit in locomotor activity. We now report that the locomotor deficit of aphakia mice is established by 40 days of age and that it can be rescued by injection of l-dopa. We further show that downstream striatal correlates of the midbrain neuronal losses in aphakia mice, as assessed by dopamine transporter binding and expression of dopamine receptors, enkephalin, dynorphin and neurotensin, are highly similar to neuroadaptive responses observed following rapid neurodegeneration induced by neurotoxin administration in adult animals or following the progressive neurodegenerative processes as seen in Parkinson patients. Taken collectively, these data support the idea that the aphakia mice represent a selective model of dopaminergic deficiency that closely resembles the midbrain and striatal neuropathology associated with Parkinson's disease, and this suggests that these mice are a good model to assess therapies for Parkinson's disease as well as to understand the susceptibility of these neurons to neurodegeneration.
van den Munckhof
Pepijn
P
Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal Québec, Canada.
Gilbert
François
F
Chamberland
Michel
M
Lévesque
Daniel
D
Drouin
Jacques
J
D000222:Adaptation, Physiological; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001035:Aphakia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001345:Autoradiography; D015415:Biomarkers; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D017403:In Situ Hybridization; D007980:Levodopa / Q000627:therapeutic use*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000473:pathology* / Q000503:physiopathology; D009479:Neuropeptides / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D010641:Phenotype; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D000978:Antiparkinson Agents; D015415:Biomarkers; D018398:Homeodomain Proteins; D009479:Neuropeptides; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D014157:Transcription Factors; C433629:homeobox protein PITX3; D007980:Levodopa