Loss of Mecp2 in Substantia Nigra Dopamine Neurons Compromises the Nigrostriatal Pathway
Open accessAbstract
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.
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The DA neurons in the substantia nigra of MECP2 mutant mice have a decreased capacitance, total dendritic length, and resting membrane conductance as early as 4 weeks after birth, well before overt neurodevelopmental symptoms are seen in the mouse model.
“In addition, the DA neurons in the substantia nigra of MECP2 mutant mice have a decreased capacitance, total dendritic length, and resting membrane conductance as early as 4 weeks after birth, well before overt neurodevelopmental symptoms are seen in the mouse model [703].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [703]
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- Authors
- Gantz, S. C., Ford, C. P., Neve, K. A., & Williams, J. T.
- Affiliations
- Oregon Health & Science University (US)
- Case Western Reserve University (US)
- Veterans Health Administration (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-08-31
- Volume
- 31
- Issue
- 35
- Pages
- 12629-12637
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3201707
- OpenAlex
- W2033700583
- Cited by
- 62
- References
- 37
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 7 · 2022: 4 · 2021: 8 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 2 · 2015: 7 · 2014: 6 · 2013: 5 · 2012: 4
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000810)
- International Rett Syndrome Foundation
- National Institutes of Health (DA026417)
- National Institute of Mental Health (R01MH045372)
- National Institute on Drug Abuse (DA026417, R00DA026417, K99DA026417, R01DA004523)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007680, DK007680)
- National Institute of Neurological Disorders and Stroke (P30NS061800, NS007466, T32NS007466)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- MeCP2, Rett syndrome, substantia nigra, dopaminergic neurons, nigrostriatal pathway, dopamine release, neuronal morphology, parkinsonian features, sex differences
- MeSH terms
- Age Factors, Analysis of Variance, Animals, Benzamides, Biophysics, Corpus Striatum, Dopamine, Electric Stimulation, Female, Gene Expression Regulation, Male, Membrane Potentials, Mice, Inbred C57BL, Neural Conduction, Neural Pathways, Neurons, Protein Binding, Radioligand Assay, Sex Factors, Substantia Nigra, Tritium, Mice, Knockout, Patch-Clamp Techniques, Dopamine Antagonists, Excitatory Amino Acid Antagonists, Mice, Methyl-CpG-Binding Protein 2, Electrochemical Techniques, In Vitro Techniques
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