MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain

Minh Vu Chuong Nguyen, Fang Du, Christy A. Felice, Xiwei Shan, Aparna Nigam, Gail Mandel, John K. Robinson, Nurit Ballas

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Mutations in the X-linked gene, methyl-CpG binding protein 2 (Mecp2), underlie a wide range of neuropsychiatric disorders, most commonly, Rett Syndrome (RTT), a severe autism spectrum disorder that affects approximately one in 10,000 female live births. Because mutations in the Mecp2 gene occur in the germ cells with onset of neurological symptoms occurring in early childhood, the role of MeCP2 has been ascribed to brain maturation at a specific developmental window. Here, we show similar kinetics of onset and progression of RTT-like symptoms in mice, including lethality, if MeCP2 is removed postnatally during the developmental stage that coincides with RTT onset, or adult stage. For the first time, we show that brains that lose MeCP2 at these two different stages are actively shrinking, resulting in higher than normal neuronal cell density. Furthermore, we show that mature dendritic arbors of pyramidal neurons are severely retracted and dendritic spine density is dramatically reduced. In addition, hippocampal astrocytes have significantly less complex ramified processes. These changes accompany a striking reduction in the levels of several synaptic proteins, including CaMKII α/β, AMPA, and NMDA receptors, and the synaptic vesicle proteins Vglut and Synapsin, which represent critical modifiers of synaptic function and dendritic arbor structure. Importantly, the mRNA levels of these synaptic proteins remains unchanged, suggesting that MeCP2 likely regulates these synaptic proteins post-transcriptionally, directly or indirectly. Our data suggest a crucial role for MeCP2 in post-transcriptional regulation of critical synaptic proteins involved in maintaining mature neuronal networks during late stages of postnatal brain development.

Original languageEnglish (US)
Pages (from-to)10021-10034
Number of pages14
JournalJournal of Neuroscience
Volume32
Issue number29
DOIs
StatePublished - Jul 18 2012

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Anatomy
Rett Syndrome
Methyl-CpG-Binding Protein 2
Brain
Proteins
Synapsins
Calcium-Calmodulin-Dependent Protein Kinase Type 2
X-Linked Genes
Dendritic Spines
Mutation
AMPA Receptors
Synaptic Vesicles
Pyramidal Cells
Live Birth
N-Methyl-D-Aspartate Receptors
Germ Cells
Astrocytes
Cell Count
Messenger RNA
Genes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. / Nguyen, Minh Vu Chuong; Du, Fang; Felice, Christy A.; Shan, Xiwei; Nigam, Aparna; Mandel, Gail; Robinson, John K.; Ballas, Nurit.

In: Journal of Neuroscience, Vol. 32, No. 29, 18.07.2012, p. 10021-10034.

Research output: Contribution to journalArticle

Nguyen, Minh Vu Chuong ; Du, Fang ; Felice, Christy A. ; Shan, Xiwei ; Nigam, Aparna ; Mandel, Gail ; Robinson, John K. ; Ballas, Nurit. / MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. In: Journal of Neuroscience. 2012 ; Vol. 32, No. 29. pp. 10021-10034.
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