Flores Gutiérrez Javier, Natali Giulia, Giorgi Jacopo, De Leonibus Elvira, Tongiorgi Enrico
Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Institute of Biochemistry and Cellular Biology (IBBC), National Research Council, Monterotondo, Rome, Italy.
Exp Neurol. 2022 Jul;353:114056. doi: 10.1016/j.expneurol.2022.114056. Epub 2022 Mar 28.
Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder, mainly caused by mutations in the MECP2 gene. Reduction in monoamine levels in RTT patients and mouse models suggested the possibility to rescue clinical phenotypes through antidepressants. Accordingly, we tested mirtazapine (MTZ), a noradrenergic and specific-serotonergic tetracyclic antidepressant (NaSSA). In previous studies, we showed high tolerability and significant positive effects of MTZ in male Mecp2-knock-out mice, adult female Mecp2-heterozygous (Mecp2) mice, and adult female RTT patients. However, it remained to explore MTZ efficacy in female Mecp2 mice at young ages. As RTT-like phenotypes in young Mecp2 mice have been less investigated, we carried out a behavioural characterization to analyze Mecp2 mice in "early adolescence" (6 weeks) and "young adulthood" (11 weeks) and identified several progressive phenotypes. Then, we evaluated the effects of either a 15- or a 30-day MTZ treatment on body weight and impaired motor behaviours in 11-week-old Mecp2 mice. Finally, since defective cortical development is a hallmark of RTT, we performed a histological study on the maturation of perineuronal nets (PNNs) and parvalbuminergic (PV) neurons in the primary motor cortex. The 30-day MTZ treatment was more effective than the shorter 15-day treatment, leading to the significant rescue of body weight, hindlimb clasping and motor learning in the accelerating rotarod test. Behavioural improvement was associated with normalized PV immunoreactivity levels and PNN thickness. These results support the use of MTZ as a new potential treatment for adolescent girls affected by RTT and suggest a possible mechanism of action.
雷特综合征（RTT）是一种罕见的X连锁神经发育障碍，主要由MECP2基因突变引起。RTT患者和小鼠模型中单胺水平的降低提示了通过抗抑郁药挽救临床表型的可能性。因此，我们测试了米氮平（MTZ），一种去甲肾上腺素能和特异性5-羟色胺能四环抗抑郁药（NaSSA）。在先前的研究中，我们表明MTZ在雄性Mecp2基因敲除小鼠、成年雌性Mecp2杂合子（Mecp2）小鼠和成年雌性RTT患者中具有高耐受性和显著的积极作用。然而，MTZ在幼年雌性Mecp2小鼠中的疗效仍有待探索。由于对幼年Mecp2小鼠中类似RTT的表型研究较少，我们进行了行为特征分析，以分析“青春期早期”（6周）和“成年早期”（11周）的Mecp2小鼠，并确定了几种进行性表型。然后，我们评估了15天或30天的MTZ治疗对11周龄Mecp2小鼠体重和运动行为受损的影响。最后，由于皮质发育缺陷是RTT的一个标志，我们对初级运动皮层中神经元周围网（PNN）和小白蛋白能（PV）神经元的成熟进行了组织学研究。30天的MTZ治疗比较短的15天治疗更有效，导致体重显著恢复、后肢紧握以及在加速转棒试验中的运动学习能力恢复。行为改善与PV免疫反应性水平和PNN厚度的正常化有关。这些结果支持将MTZ用作治疗受RTT影响的青春期女孩的一种新的潜在疗法，并提示了一种可能的作用机制。
