Zhong Weiwei, Johnson Christopher Mychal, Wu Yang, Cui Ningren, Xing Hao, Zhang Shuang, Jiang Chun
Department of Biology, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30302-4010 USA.
J Neurodev Disord. 2016 Oct 19;8:37. doi: 10.1186/s11689-016-9169-2. eCollection 2016.
Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the gene. -null mice show imbalances in neuronal excitability and synaptic communications. Several previous studies indicate that augmenting synaptic GABA receptors (GABARs) can alleviate RTT-like symptoms in mice. In addition to the synaptic GABARs, there is a group of GABARs found outside the synaptic cleft with the capability to produce sustained inhibition, which may be potential therapeutic targets for the control of neuronal excitability in RTT.
Wild-type and -null mice were randomly divided into four groups, receiving the extrasynaptic GABAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-]pyridin-3-ol hydrochloride (THIP) and vehicle control, respectively. Low-dose THIP was administered to neonatal mice through lactation. RTT-like symptoms including lifespan, breathing, motor function, and social behaviors were studied when mice became mature. Changes in neuronal excitability and norepinephrine biosynthesis enzyme expression were studied in electrophysiology and molecular biology.
With no evident sedation and other adverse side effects, early-life exposure to THIP extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors of -null mice. Such beneficial effects were associated with stabilization of locus coeruleus neuronal excitability and improvement of norepinephrine biosynthesis enzyme expression.
THIP treatment in early lives might be a therapeutic approach to RTT-like symptoms in -null mice and perhaps in people with RTT as well.
雷特综合征（RTT）是一种主要由基因破坏引起的神经发育障碍。基因敲除小鼠表现出神经元兴奋性和突触通讯的失衡。先前的几项研究表明，增强突触GABA受体（GABARs）可以减轻小鼠的雷特综合征样症状。除了突触GABARs外，在突触间隙外还发现了一组具有产生持续抑制能力的GABARs，它们可能是控制雷特综合征中神经元兴奋性的潜在治疗靶点。
将野生型和基因敲除小鼠随机分为四组，分别接受突触外GABAR激动剂盐酸4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇（THIP）和溶剂对照。低剂量THIP通过哺乳给予新生小鼠。当小鼠成熟时，研究包括寿命、呼吸、运动功能和社交行为在内的雷特综合征样症状。通过电生理学和分子生物学研究神经元兴奋性和去甲肾上腺素生物合成酶表达的变化。
在没有明显镇静和其他不良副作用的情况下，生命早期暴露于THIP可延长基因敲除小鼠的寿命，减轻呼吸异常，增强运动功能，并改善社交行为。这些有益效果与蓝斑神经元兴奋性的稳定和去甲肾上腺素生物合成酶表达的改善有关。
生命早期的THIP治疗可能是治疗基因敲除小鼠雷特综合征样症状的一种方法，也许对雷特综合征患者也有效。
