A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome.
A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome.
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DOI：
10.1523/jneurosci.0865-11.2012
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
Katz DM
中科院分区：
文献类型：
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作者：
Schmid DA;Yang T;Ogier M;Adams I;Mirakhur Y;Wang Q;Massa SM;Longo FM;Katz DM
Rett综合征（RTT）是由编码甲基CpG结合蛋白2（MeCP 2）的基因的功能缺失突变引起的，其特征在于运动、呼吸和自主控制异常、认知障碍、自闭症样行为和癫痫发作风险增加。RTT患者和Mecp 2缺失小鼠表现出脑源性神经营养因子（BDNF）表达减少，这在小鼠中与呼吸频率增加有关，呼吸频率增加是RTT的标志。本研究旨在验证Mecp 2突变体中BDNF缺陷与BDNF受体TrkB激活减少相关的假设，以及TrkB的药理学激活将改善呼吸功能。我们在杂合子雌性Mecp 2突变小鼠（Het）中表征了BDNF蛋白表达、TrkB激活和呼吸，该模型概括了在典型RTT患者中发现的突变Mecp 2的体细胞嵌合现象，并评估了小分子TrkB激动剂LM 22 A-4改善这些动物中生化和功能异常的能力。我们发现，Het小鼠表现出1）髓质和脑桥中BDNF表达和TrkB活化减少，以及2）呼吸功能障碍，其特征在于由于呼吸急促周期而导致的频率增加，以及呼吸暂停增加，如RTT患者中那样。用LM 22 A-4治疗Het小鼠4周，挽救了髓质和脑桥中TrkB磷酸化的野生型水平，并恢复了野生型呼吸频率。这些数据提供了新的见解，BDNF信号转导缺陷的RTT的病理生理学的作用，并强调TrkB作为一个可能的治疗靶点在这种疾病。
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 wildtype levels of TrkB phosphorylation in the medulla and pons and restored wildtype 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.