Document Detail

Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment.
MedLine Citation:
PMID:  23035095     Owner:  NLM     Status:  MEDLINE    
Excitatory-inhibitory imbalance has been identified within specific brain microcircuits in models of Rett syndrome (RTT) and other autism spectrum disorders (ASDs). However, macrocircuit dysfunction across the RTT brain as a whole has not been defined. To approach this issue, we mapped expression of the activity-dependent, immediate-early gene product Fos in the brains of wild-type (Wt) and methyl-CpG-binding protein 2 (Mecp2)-null (Null) mice, a model of RTT, before and after the appearance of overt symptoms (3 and 6 weeks of age, respectively). At 6 weeks, Null mice exhibit significantly less Fos labeling than Wt in limbic cortices and subcortical structures, including key nodes in the default mode network. In contrast, Null mice exhibit significantly more Fos labeling than Wt in the hindbrain, most notably in cardiorespiratory regions of the nucleus tractus solitarius (nTS). Using nTS as a model, whole-cell recordings demonstrated that increased Fos expression in Nulls at 6 weeks of age is associated with synaptic hyperexcitability, including increased frequency of spontaneous and miniature EPSCs and increased amplitude of evoked EPSCs in Nulls. No such effect of genotype on Fos or synaptic function was seen at 3 weeks. In the mutant forebrain, reduced Fos expression, as well as abnormal sensorimotor function, were reversed by the NMDA receptor antagonist ketamine. In light of recent findings that the default mode network is hypoactive in autism, our data raise the possibility that hypofunction within this meta-circuit is a shared feature of RTT and other ASDs and is reversible.
Miriam Kron; C James Howell; Ian T Adams; Michael Ransbottom; Diana Christian; Michael Ogier; David M Katz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  32     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-04     Completed Date:  2013-01-17     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13860-72     Citation Subset:  IM    
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
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MeSH Terms
Autonomic Nervous System / physiopathology*
Cerebellum / metabolism,  physiopathology
Disease Models, Animal
Excitatory Amino Acid Antagonists / pharmacology*
Gene Expression Regulation, Developmental
Genes, fos
Ketamine / pharmacology*
Methyl-CpG-Binding Protein 2 / deficiency,  genetics,  physiology*
Mice, Knockout
Miniature Postsynaptic Potentials / drug effects,  physiology
Nerve Net / drug effects,  metabolism,  physiopathology*
Nerve Tissue Proteins / biosynthesis,  genetics,  physiology
Organ Specificity
Patch-Clamp Techniques
Prosencephalon / metabolism,  physiopathology*
Proto-Oncogene Proteins c-fos / biosynthesis
Rett Syndrome / genetics,  physiopathology
Sensory Gating / drug effects,  physiology
Solitary Nucleus / chemistry,  metabolism,  physiopathology*
Synaptic Transmission / drug effects,  physiology
Grant Support
Reg. No./Substance:
0/Excitatory Amino Acid Antagonists; 0/Mecp2 protein, mouse; 0/Methyl-CpG-Binding Protein 2; 0/Nerve Tissue Proteins; 0/Proto-Oncogene Proteins c-fos; 6740-88-1/Ketamine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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