Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate

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Abstract

MECP2, an X-linked gene encoding the epigenetic factor methyl-CpG-binding protein-2, is mutated in Rett syndrome (RTT) and aberrantly expressed in autism. Most children affected by RTT are heterozygous Mecp2-/+ females whose brain function is impaired postnatally due to MeCP2 deficiency. Recent studies suggest a role of glia in causing neuronal dysfunction via a non-cell-autonomous effect in RTT. Here we report a potent neurotoxic activity in the conditioned medium (CM) obtained from Mecp2-null microglia. Hippocampal neurons treated withCMfrom Mecp2-null microglia showed an abnormal stunted and beaded dendritic morphology, and signs of microtubule disruption and damage of postsynaptic glutamatergic components within 24 h. We identified that the toxic factor in the CM is glutamate, because (1) Mecp2-null microglia released a fivefold higher level of glutamate, (2) blockage of microglial glutamate synthesis by a glutaminase inhibitor abolished the neurotoxic activity, (3) blockage of microglial glutamate release by gap junction hemichannel blockers abolished the neurotoxic activity, and (4) glutamate receptor antagonists blocked the neurotoxicity of the Mecp2-null microglia CM.Wefurther identified that increased levels of glutaminase and connexin 32 in Mecp2-null microglia are responsible for increased glutamate production and release, respectively. In contrast, theCMfrom highly pure Mecp2-null astrocyte cultures showed no toxic effect. Our results suggest that microglia may influence the onset and progression of RTT and that microglia glutamate synthesis or release could be a therapeutic target for RTT.

Original languageEnglish (US)
Pages (from-to)5346-5356
Number of pages11
JournalJournal of Neuroscience
Volume30
Issue number15
DOIs
StatePublished - Apr 14 2010

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Rett Syndrome
Microglia
Dendrites
Synapses
Glutamic Acid
Conditioned Culture Medium
Glutaminase
Poisons
Methyl-CpG-Binding Protein 2
Excitatory Amino Acid Antagonists
X-Linked Genes
Gap Junctions
Autistic Disorder
Epigenomics
Microtubules
Neuroglia
Astrocytes
Neurons
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. / Maezawa, Izumi; Jin, Lee-Way.

In: Journal of Neuroscience, Vol. 30, No. 15, 14.04.2010, p. 5346-5356.

Research output: Contribution to journalArticle

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