PDF(Pubmed)
Abstract：
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.
摘要：
Rett综合征（RTT）是由MECP2突变引起的神经发育障碍，它编码甲基CpG结合蛋白2，是许多基因的转录调节因子，包括脑源性神经营养因子（BDNF）。在Mecp2缺陷小鼠的多个脑区，BDNF水平较低，通过实验增加BDNF水平可以改善Mecp2突变小鼠的非典型表型。由于BDNF本身的血脑屏障通透性较低，我们测试了LM22A-4的效果，一种脑渗透剂，BDNF受体TrkB的小分子配体（由Ntrk2编码），对雌性Mecp2杂合（HET）小鼠的海马锥体神经元的树突棘密度和形态以及行为表型的影响。用LM22A-4对Mecp2HET小鼠进行为期4周的全身治疗，将MeCP2表达神经元的脊柱体积恢复到野生型（WT）水平，而缺乏MeCP2的神经元的脊柱体积仍与雌性WT小鼠的神经元相当。雌性Mecp2HET小鼠比WT小鼠更有攻击行为，通过4周的LM22A-4治疗，其水平降低至WT水平。这些数据为新疗法不仅对RTT而且对其他BDNF相关疾病的潜在有用性提供了额外的支持。
