TY - JOUR T1 - Loss of Mecp2 in Substantia Nigra Dopamine Neurons Compromises the Nigrostriatal Pathway JF - The Journal of Neuroscience JO - J. Neurosci. SP - 12629 LP - 12637 DO - 10.1523/JNEUROSCI.0684-11.2011 VL - 31 IS - 35 AU - Stephanie C. Gantz AU - Christopher P. Ford AU - Kim A. Neve AU - John T. Williams Y1 - 2011/08/31 UR - http://www.jneurosci.org/content/31/35/12629.abstract N2 - 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 D2 dopamine autoreceptors was significantly less in Mecp2− neurons than in Mecp2+ neurons, although D2 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 D2 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. ER -