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

• Published in: The Journal of neuroscience Vol. 31; no. 35; pp. 12629 - 12637
• Main Authors: Gantz, Stephanie C, Ford, Christopher P, Neve, Kim A, Williams, John T
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 31-08-2011
• Subjects: Age Factors; Analysis of Variance; Animals; Benzamides - pharmacokinetics; Biophysics; Corpus Striatum - physiology; Dopamine - metabolism; Dopamine Antagonists - pharmacokinetics; Electric Stimulation - methods; Electrochemical Techniques - methods; Excitatory Amino Acid Antagonists - pharmacology; Female; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; In Vitro Techniques; Male; Membrane Potentials - drug effects; Membrane Potentials - genetics; Methyl-CpG-Binding Protein 2 - deficiency; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Conduction - drug effects; Neural Conduction - genetics; Neural Pathways - physiology; Neurons - drug effects; Neurons - physiology; Patch-Clamp Techniques - methods; Protein Binding - drug effects; Radioligand Assay; Sex Factors; Substantia Nigra - cytology; Tritium - pharmacokinetics
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.0684-11.2011

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.