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.