Molecular and cellular alterations in the Pitx3-deficient midbrain dopaminergic system.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of midbrain dopaminergic (mDA) neurons in the substantia nigra compacta (SNc). In order to provide insights into adaptive mechanisms of the mDA system in pathology, specific molecular and cellular parameters of the mDA system were studied in Pitx3-deficient Aphakia (ak) mice, which suffer from severe developmental failure of SNc mDA neurons. Here, we demonstrate differential changes in striatal gene expression, reflecting the specific neuronal loss in these mice. In addition, the neuronal activity of remaining mDA neurons in the ventral tegmental area (VTA) was significantly increased in ak mice. In conclusion, ak mice display specific molecular and cellular alterations in the mDA system that provide new insights in compensatory mechanisms present in mDA-associated disorders such as PD.
Smits
Simone M
SM
Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Mathon
Daniel S
DS
Burbach
J Peter H
JP
Ramakers
Geert M J
GM
Smidt
Marten P
MP
D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D017072:Neostriatum / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D009434:Neural Pathways / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D013378:Substantia Nigra / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D017557:Ventral Tegmental Area / Q000254:growth & development / Q000378:metabolism
D018398:Homeodomain Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D014157:Transcription Factors; C433629:homeobox protein PITX3; D004298:Dopamine