Journal article
Loss of Mecp2 in Substantia Nigra Dopamine Neurons Compromises the Nigrostriatal Pathway
The Journal of neuroscience, Vol.31(35), pp.12629-12637
08/31/2011
DOI: 10.1523/JNEUROSCI.0684-11.2011
PMCID: PMC3201707
PMID: 21880923
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.
Details
- Title: Subtitle
- Loss of Mecp2 in Substantia Nigra Dopamine Neurons Compromises the Nigrostriatal Pathway
- Creators
- Stephanie C Gantz - Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239Christopher P Ford - Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106, andKim A Neve - Research Service, Department of Veterans Affairs Medical Center, Portland, Oregon 97239John T Williams - Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.31(35), pp.12629-12637
- Publisher
- Society for Neuroscience
- DOI
- 10.1523/JNEUROSCI.0684-11.2011
- PMID
- 21880923
- PMCID
- PMC3201707
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Language
- English
- Date published
- 08/31/2011
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984065466302771
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