Molecular and Cellular Alterations in the Pitx3-deficient Midbrain Dopaminergic System

Mol Cell Neurosci. 2005 Nov;30(3):352-63. doi: 10.1016/j.mcn.2005.07.018. Epub 2005 Sep 6.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / genetics
  • Animals
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Dopamine / pharmacology
  • Gene Expression Regulation, Developmental / genetics
  • Homeodomain Proteins / genetics*
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Neostriatum / growth & development
  • Neostriatum / metabolism*
  • Neostriatum / physiopathology
  • Neural Pathways / abnormalities*
  • Neural Pathways / metabolism
  • Neural Pathways / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology
  • Patch-Clamp Techniques
  • Receptors, Dopamine D1 / drug effects
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism
  • Substantia Nigra / abnormalities*
  • Substantia Nigra / metabolism
  • Substantia Nigra / physiopathology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • Ventral Tegmental Area / growth & development
  • Ventral Tegmental Area / metabolism

Substances

  • Homeodomain Proteins
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Transcription Factors
  • homeobox protein PITX3
  • Dopamine