A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome.
Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.
Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Danielle A
DA
Schmid
Tao
T
Yang
Michael
M
Ogier
Ian
I
Adams
Yatin
Y
Mirakhur
Qifang
Q
Wang
Stephen M
SM
Massa
Frank M
FM
Longo
David M
DM
Katz
D000818:Animals; D001549:Benzamides / Q000378:metabolism*; D004195:Disease Models, Animal; D054333:Drug Partial Agonism; D005260:Female; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D020813:Receptor, trkB / Q000819:agonists* / Q000378:metabolism*; D015656:Respiratory Mechanics / Q000187:drug effects* / Q000235:genetics; D015518:Rett Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; C585903:N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide; D020813:Receptor, trkB