A small-molecule TrkB ligand restores hippocampal synaptic plasticity and object location memory in Rett syndrome mice.
A small-molecule TrkB ligand restores hippocampal synaptic plasticity and object location memory in Rett syndrome mice.
复制标题
DOI：
10.1242/dmm.029959
复制
发表时间：
2017-07-01
影响因子：
4.3
通讯作者：
Pozzo-Miller L
中科院分区：
文献类型：
--
作者：
Li W;Bellot-Saez A;Phillips ML;Yang T;Longo FM;Pozzo-Miller L
Rett综合征（RTT）是一种由甲基cpg结合蛋白-2 （MECP2）突变引起的神经发育障碍，MECP2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RTT尸检大脑和mecp2缺陷小鼠的多个脑区中，BDNF水平降低。此外，增加BDNF水平的实验干预可以改善Mecp2突变小鼠的rtt样表型。在这里，我们表征了BDNF受体TrkB的小分子配体在Mecp2突变小鼠海马功能中的作用。用LM22A-4全身治疗雌性Mecp2杂合（HET）小鼠4周后，海马依赖的物体定位记忆得到改善，海马长期增强（LTP）得到恢复。在机制上，LM22A-4抑制过度活跃的海马网络活动，降低微型兴奋性突触后电流（mEPSCs）的频率和幅度，并降低Mecp2突变海马神经元中自发河豚毒素抗性Ca2+信号的频率，使其与野生型神经元中观察到的特征相当。总之，这些观察结果表明LM22A-4是治疗RTT海马功能障碍的有希望的治疗候选者。编者选择：脑穿透性BDNF环结构域模拟物LM22A-4改善Rett综合征小鼠突触可塑性和空间辨别记忆，使其成为治疗海马功能障碍的有希望的治疗候选者。
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein-2 (MECP2), a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are reduced in RTT autopsy brains and in multiple brain areas of Mecp2-deficient mice. Furthermore, experimental interventions that increase BDNF levels improve RTT-like phenotypes in Mecp2 mutant mice. Here, we characterized the actions of a small-molecule ligand of the BDNF receptor TrkB in hippocampal function in Mecp2 mutant mice. Systemic treatment of female Mecp2 heterozygous (HET) mice with LM22A-4 for 4 weeks improved hippocampal-dependent object location memory and restored hippocampal long-term potentiation (LTP). Mechanistically, LM22A-4 acts to dampen hyperactive hippocampal network activity, reduce the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), and reduce the frequency of spontaneous tetrodotoxin-resistant Ca2+ signals in Mecp2 mutant hippocampal neurons, making them comparable to those features observed in wild-type neurons. Together, these observations indicate that LM22A-4 is a promising therapeutic candidate for the treatment of hippocampal dysfunction in RTT. Editors' choice: The brain-penetrant BDNF loop domain mimetic LM22A-4 improves synaptic plasticity and spatial discrimination memory in Rett syndrome mice, making it a promising therapeutic candidate for the treatment of hippocampal dysfunction.
登录
查看更多内容
影响因子：
8.3
作者：
Han J;Pollak J;Yang T;Siddiqui MR;Doyle KP;Taravosh-Lahn K;Cekanaviciute E;Han A;Goodman JZ;Jones B;Jing D;Massa SM;Longo FM;Buckwalter MS
通讯作者：
Buckwalter MS
影响因子：
5.3
作者：
Amaral, Michelle D.;Pozzo-Miller, Lucas
通讯作者：
Pozzo-Miller, Lucas
影响因子：
3.5
作者：
Deng, Vivianne;Matagne, Valerie;Ojeda, Sergio R.
通讯作者：
Ojeda, Sergio R.
影响因子：
16.2
作者：
Chang, QA;Khare, G;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
6.1
作者：
Chapleau CA;Calfa GD;Lane MC;Albertson AJ;Larimore JL;Kudo S;Armstrong DL;Percy AK;Pozzo-Miller L
通讯作者：
Pozzo-Miller L