• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

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

Authors

  • Gantz SC
  • Ford CP
  • Neve KA
  • Williams JT

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

August 31, 2011

Associated Grants

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

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