title: Loss of Mecp2 in substantia nigra dopamine neurons compromises the nigrostriatal pathway.
abstract: 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.
authors: Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors: Stephanie C
authors: SC
authors: Gantz
authors: Christopher P
authors: CP
authors: Ford
authors: Kim A
authors: KA
authors: Neve
authors: John T
authors: JT
authors: Williams
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics; D001703:Biophysics; D003342:Corpus Striatum / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D004558:Electric Stimulation / Q000379:methods; D055664:Electrochemical Techniques / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009431:Neural Conduction / Q000187:drug effects / Q000235:genetics; D009434:Neural Pathways / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D012737:Sex Factors; D013378:Substantia Nigra / Q000166:cytology*; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D001549:Benzamides; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D014316:Tritium; C030265:nemonapride; D004298:Dopamine