Li Wei, Bellot-Saez Alba, Phillips Mary L, Yang Tao, Longo Frank M, Pozzo-Miller Lucas
Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Dis Model Mech. 2017 Jul 1;10(7):837-845. doi: 10.1242/dmm.029959.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein-2 (), a transcriptional regulator of many genes, including brain-derived neurotrophic factor (). BDNF levels are reduced in RTT autopsy brains and in multiple brain areas of -deficient mice. Furthermore, experimental interventions that increase BDNF levels improve RTT-like phenotypes in mutant mice. Here, we characterized the actions of a small-molecule ligand of the BDNF receptor TrkB in hippocampal function in mutant mice. Systemic treatment of female 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 Ca signals in 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.
雷特综合征（RTT）是一种神经发育障碍，由甲基-CpG结合蛋白2（MeCP2）突变引起，MeCP2是许多基因（包括脑源性神经营养因子，BDNF）的转录调节因子。在雷特综合征尸检大脑以及MeCP2缺陷小鼠的多个脑区中，BDNF水平均降低。此外，提高BDNF水平的实验性干预可改善MeCP2突变小鼠的类雷特综合征表型。在此，我们在MeCP2突变小鼠的海马功能中表征了BDNF受体TrkB的小分子配体的作用。用LM22A-4对雌性MeCP2杂合（HET）小鼠进行4周的全身治疗，改善了海马依赖性物体位置记忆，并恢复了海马长时程增强（LTP）。从机制上讲，LM22A-4的作用是抑制海马网络活动亢进，降低微小兴奋性突触后电流（mEPSCs）的频率和幅度，并降低MeCP2突变海马神经元中耐河豚毒素的Ca信号的频率，使其与野生型神经元中观察到的这些特征相当。总之，这些观察结果表明，LM22A-4是治疗雷特综合征中海马功能障碍的有前景的治疗候选物。
