Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome.
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.
Ogier
Michael
M
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Wang
Hong
H
Hong
Elizabeth
E
Wang
Qifang
Q
Greenberg
Michael E
ME
Katz
David M
DM
D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D047630:Depsipeptides / Q000187:drug effects*; D004149:Dioxoles / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009620:Nodose Ganglion / Q000166:cytology; D010880:Piperidines / Q000627:therapeutic use*; D010991:Plethysmography / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D015518:Rett Syndrome / Q000188:drug therapy* / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013779:Tetrodotoxin / Q000494:pharmacology
C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D000779:Anesthetics, Local; D019208:Brain-Derived Neurotrophic Factor; D047630:Depsipeptides; D004149:Dioxoles; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D010880:Piperidines; D012333:RNA, Messenger; C081425:respirantin; D013779:Tetrodotoxin