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Brain-Derived Neurotrophic Factor Expression and Respiratory Function Improve after Ampakine Treatment in a Mouse Model of Rett Syndrome

Ogier, Michael and Wang, Hong and Hong, Elizabeth J. and Wang, Qifang and Greenberg, Michael E. and Katz, David M. (2007) Brain-Derived Neurotrophic Factor Expression and Respiratory Function Improve after Ampakine Treatment in a Mouse Model of Rett Syndrome. Journal of Neuroscience, 27 (40). pp. 10912-10917. ISSN 0270-6474. PMCID PMC6672830. doi:10.1523/JNEUROSCI.1869-07.2007.

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Rett syndrome (RTT) is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is thought to act as a transcriptional repressor of brain-derived neurotrophic factor (BDNF), Mecp2 null mice, which develop an RTT-like phenotype, exhibit progressive deficits in BDNF expression. These deficits are particularly significant in the brainstem and nodose cranial sensory ganglia (NGs), structures critical for cardiorespiratory homeostasis, and may be linked to the severe respiratory abnormalities characteristic of RTT. Therefore, the present study used Mecp2 null mice to further define the role of MeCP2 in regulation of BDNF expression and neural function, focusing on NG neurons and respiratory control. We find that mutant neurons express significantly lower levels of BDNF than wild-type cells in vitro, as in vivo, under both depolarizing and nondepolarizing conditions. However, BDNF levels in mutant NG cells can be increased by chronic depolarization in vitro or by treatment of Mecp2 null mice with CX546, an ampakine drug that facilitates activation of glutamatergic AMPA receptors. Ampakine-treated Mecp2 null mice also exhibit marked functional improvement, characterized by restoration of normal breathing frequency and minute volume. These data demonstrate that BDNF expression remains plastic in Mecp2 null mice and raise the possibility that ampakine compounds could be of therapeutic value in the treatment of RTT.

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Additional Information:© 2007 Society for Neuroscience. Beginning six months after publication the Work will be made freely available to the public on SfN’s website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license ( Received April 24, 2007. Revision received August 3, 2007. Accepted August 20, 2007. This work was supported by grants from the National Heart, Lung, and Blood Institute; the Rett Syndrome Research Foundation; and the National Institutes of Health to D.M.K. and M.E.G. We gratefully acknowledge Dr. Diana Kunze for critical review of this manuscript and David T. Hellard for technical help.
Funding AgencyGrant Number
National Heart, Lung and Blood InstituteUNSPECIFIED
Rett Syndrome Research FoundationUNSPECIFIED
Subject Keywords:Mecp2 null mice; respiratory frequency; minute volume; nodose ganglion; neurotrophin expression; AMPA receptors modulator
Issue or Number:40
PubMed Central ID:PMC6672830
Record Number:CaltechAUTHORS:20151005-163319702
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Official Citation:Brain-Derived Neurotrophic Factor Expression and Respiratory Function Improve after Ampakine Treatment in a Mouse Model of Rett Syndrome Michael Ogier, Hong Wang, Elizabeth Hong, Qifang Wang, Michael E. Greenberg, and David M. Katz The Journal of Neuroscience, 3 October 2007, 27(40): 10912-10917; doi: 10.1523/JNEUROSCI.1869-07.2007
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:60788
Deposited By: George Porter
Deposited On:06 Oct 2015 15:02
Last Modified:10 Nov 2021 22:39

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