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Loss of Mecp2 in substantia nigra dopamine neurons compromises the nigrostriatal pathway.

Mutations in the methyl-CpG-binding protein 2 (MeCP2) result in Rett syndrome (RTT), an X-linked disorder that disrupts neurodevelopment. Girls with RTT exhibit motor deficits similar to those in Parkinson's disease, suggesting defects in the nigrostriatal pathway. This study examined age-dependent changes in dopamine neurons of the substantia nigra (SN) from wild-type, presymptomatic, and symptomatic Mecp2(+/-) mice. Mecp2(+) neurons in the SN in Mecp2(+/-) mice were indistinguishable in morphology, resting conductance, and dopamine current density from neurons in wild-type mice. However, the capacitance, total dendritic length, and resting conductance of Mecp2(-) neurons were less than those of Mecp2(+) neurons as early as 4 weeks after birth, before overt symptoms. These differences were maintained throughout life. In symptomatic Mecp2(+/-) mice, the current induced by activation of D(2) dopamine autoreceptors was significantly less in Mecp2(-) neurons than in Mecp2(+) neurons, although D(2) receptor density was unaltered in Mecp2(+/-) mice. Electrochemical measurements revealed that significantly less dopamine was released after stimulation of striatum in adult Mecp2(+/-) mice compared to wild type. The decrease in size and function of Mecp2(-) neurons observed in adult Mecp2(+/-) mice was recapitulated in dopamine neurons from symptomatic Mecp2(-/y) males. These results show that mutation in Mecp2 results in cell-autonomous defects in the SN early in life and throughout adulthood. Ultimately, dysfunction in terminal dopamine release and D(2) autoreceptor-dependent currents in dopamine neurons from symptomatic females support the idea that decreased dopamine transmission due to heterogeneous Mecp2 expression contributes to the parkinsonian features of RTT in Mecp2(+/-) mice.

Pubmed ID: 21880923 RIS Download

Mesh terms: Age Factors | Analysis of Variance | Animals | Benzamides | Biophysics | Corpus Striatum | Dopamine | Dopamine Antagonists | Electric Stimulation | Electrochemical Techniques | Excitatory Amino Acid Antagonists | Female | Gene Expression Regulation | In Vitro Techniques | Male | Membrane Potentials | Methyl-CpG-Binding Protein 2 | Mice | Mice, Inbred C57BL | Mice, Knockout | Neural Conduction | Neural Pathways | Neurons | Patch-Clamp Techniques | Protein Binding | Radioligand Assay | Sex Factors | Substantia Nigra | Tritium

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Associated grants

  • Agency: NIDA NIH HHS, Id: R01 DA004523-25
  • Agency: NIDDK NIH HHS, Id: DK007680
  • Agency: NIMH NIH HHS, Id: R01 MH045372
  • Agency: NIDA NIH HHS, Id: R01 DA004523
  • Agency: NIDA NIH HHS, Id: DA026417
  • Agency: NIDA NIH HHS, Id: K99 DA026417
  • Agency: NIDDK NIH HHS, Id: T32 DK007680
  • Agency: NIDA NIH HHS, Id: R00 DA026417
  • Agency: BLRD VA, Id: I01 BX000810
  • Agency: NINDS NIH HHS, Id: NS007466
  • Agency: NIDA NIH HHS, Id: R00 DA026417-03
  • Agency: NINDS NIH HHS, Id: T32 NS007466
  • Agency: NINDS NIH HHS, Id: P30 NS061800

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