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PLoS One. 2014 Mar 18;9(3):e91148. doi: 10.1371/journal.pone.0091148. eCollection 2014.

Network models predict that reduced excitatory fluctuations can give rise to hippocampal network hyper-excitability in MeCP2-null mice.

Author information

1
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
2
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Surgery (Neurosurgery), University of Toronto, Toronto, Ontario, Canada.
3
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada.
4
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada.

Erratum in

  • PLoS One. 2014;9(7):e103906.

Abstract

Rett syndrome is a severe pediatric neurological disorder caused by loss of function mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2). Although MeCP2 is expressed near ubiquitously, the primary pathophysiology of Rett syndrome stems from impairments of nervous system function. One alteration within different regions of the MeCP2-deficient brain is the presence of hyper-excitable network responses. In the hippocampus, such responses exist despite there being an overall decrease in spontaneous excitatory drive within the network. In this study, we generated and used mathematical, neuronal network models to resolve this apparent paradox. We did this by taking advantage of previous mathematical modelling insights that indicated that decreased excitatory fluctuations, but not mean excitatory drive, more critically explain observed changes in hippocampal network oscillations from MeCP2-null mouse slices. Importantly, reduced excitatory fluctuations could also bring about hyper-excitable responses in our network models. Therefore, these results indicate that diminished excitatory fluctuations may be responsible for the hyper-excitable state of MeCP2-deficient hippocampal circuitry.

PMID:
24642514
PMCID:
PMC3958347
DOI:
10.1371/journal.pone.0091148
[Indexed for MEDLINE]
Free PMC Article

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