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Genotype-specific effects of Mecp2 loss-of-function on morphology of Layer V pyramidal neurons in heterozygous female Rett syndrome model mice

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Rietveld, Leslie, Stuss, David P., McPhee, David, Delaney, Kerry R.·2015·Frontiers in Cellular Neuroscience
DOI 10.3389/fncel.2015.00145PMC PMC4403522
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Abstract

Rett syndrome (RTT) is a progressive neurological disorder primarily caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). The heterozygous female brain consists of mosaic of neurons containing both wild-type MeCP2 (MeCP2+) and mutant MeCP2 (MeCP2-). Three-dimensional morphological analysis was performed on individually genotyped layer V pyramidal neurons in the primary motor cortex of heterozygous (Mecp2(+/-) ) and wild-type (Mecp2(+/+) ) female mice ( > 6 mo.) from the Mecp2(tm1.1Jae) line. Comparing basal dendrite morphology, soma and nuclear size of MeCP2+ to MeCP2- neurons reveals a significant cell autonomous, genotype specific effect of Mecp2. MeCP2- neurons have 15% less total basal dendritic length, predominantly in the region 70-130 μm from the cell body and on average three fewer branch points, specifically loss in the second and third branch orders. Soma and nuclear areas of neurons of mice were analyzed across a range of ages (5-21 mo.) and X-chromosome inactivation (XCI) ratios (12-56%). On average, MeCP2- somata and nuclei were 15 and 13% smaller than MeCP2+ neurons respectively. In most respects branching morphology of neurons in wild-type brains (MeCP2 WT) was not distinguishable from MeCP2+ but somata and nuclei of MeCP2 WT neurons were larger than those of MeCP2+ neurons. These data reveal cell autonomous effects of Mecp2 mutation on dendritic morphology, but also suggest non-cell autonomous effects with respect to cell size. MeCP2+ and MeCP2- neuron sizes were not correlated with age, but were correlated with XCI ratio. Unexpectedly the MeCP2- neurons were smallest in brains where the XCI ratio was highly skewed toward MeCP2+, i.e., wild-type. This raises the possibility of cell non-autonomous effects that act through mechanisms other than globally secreted factors; perhaps competition for synaptic connections influences cell size and morphology in the genotypically mosaic brain of RTT model mice.

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  • Dysregulation of extracellular ATP is involved in depression-like disorders in rodents.

    “Our data further validate that the dysregulation of extracellular ATP, a significant mediator of astrocyte-neuron communications [61, 62], is involved in depression-like disorders in rodents [24, 63, 64].”

    From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [63]

    The Introduction and Abstract discuss Rett syndrome and neuronal morphology, not extracellular ATP or depression-like disorders. Searches of our complete indexed copy for extracellular ATP and depression-like behavior found no passage addressing the claimed link in rodents. (LLM, conf=0.77)

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Authors
Rietveld, L., Stuss, D. P., McPhee, D., & Delaney, K. R.
Affiliations
University of Victoria (CA)
Corresponding author
Delaney, Kerry R.
ORCID
Delaney, Kerry R.
Venue
Frontiers in Cellular Neuroscience
Publisher
Frontiers Media SA
Published
2015-04-20
Volume
9
Pages
145-145
ISSN
1662-5102 (ISSN-L)
DOI
10.3389/fncel.2015.00145
PMC
PMC4403522
OpenAlex
W2042726318
Cited by
39
References
2
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 1 · 2018: 1 · 2017: 5 · 2016: 5
FWCI
2.27
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
International Rett Syndrome Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
Rett syndrome, MeCP2, layer 5 pyramidal neurons, dendritic morphology, neuronal soma size, nuclear size, X chromosome inactivation, cell-autonomous effects, non-cell-autonomous effects, primary motor cortex, dendritic branching

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