Gory-Fauré Sylvie, Powell Rebecca, Jonckheere Julie, Lanté Fabien, Denarier Eric, Peris Leticia, Nguyen Chi Hung, Buisson Alain, Lafanechère Laurence, Andrieux Annie
Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France.
Université Grenoble Alpes, Grenoble, France.
Front Pharmacol. 2021 Mar 12;12:627995. doi: 10.3389/fphar.2021.627995. eCollection 2021.
The search for effective treatments for neuropsychiatric disorders is ongoing, with progress being made as brain structure and neuronal function become clearer. The central roles played by microtubules (MT) and actin in synaptic transmission and plasticity suggest that the cytoskeleton and its modulators could be relevant targets for the development of new molecules to treat psychiatric diseases. In this context, LIM Kinase - which regulates both the actin and MT cytoskeleton especially in dendritic spines, the post-synaptic compartment of the synapse - might be a good target. In this study, we analyzed the consequences of blocking LIMK1 pharmacologically using Pyr1. We investigated synaptic plasticity defects and behavioral disorders in MAP6 KO mice, an animal model useful for the study of psychiatric disorders, particularly schizophrenia. Our results show that Pyr1 can modulate MT dynamics in neurons. In MAP6 KO mice, chronic LIMK inhibition by long-term treatment with Pyr1 can restore normal dendritic spine density and also improves long-term potentiation, both of which are altered in these mice. Pyr1 treatment improved synaptic plasticity, and also reduced social withdrawal and depressive/anxiety-like behavior in MAP6 KO mice. Overall, the results of this study validate the hypothesis that modulation of LIMK activity could represent a new therapeutic strategy for neuropsychiatric diseases.
针对神经精神疾病有效治疗方法的探索仍在继续，随着脑结构和神经元功能日益清晰，研究取得了进展。微管（MT）和肌动蛋白在突触传递和可塑性中发挥的核心作用表明，细胞骨架及其调节剂可能是开发治疗精神疾病新分子的相关靶点。在这种背景下，LIM激酶——特别是在树突棘（突触的突触后部分）中调节肌动蛋白和MT细胞骨架——可能是一个很好的靶点。在本研究中，我们分析了使用Pyr1药理学阻断LIMK1的后果。我们研究了MAP6基因敲除小鼠（一种对研究精神疾病，特别是精神分裂症有用的动物模型）的突触可塑性缺陷和行为障碍。我们的结果表明，Pyr1可以调节神经元中的MT动力学。在MAP6基因敲除小鼠中，通过长期用Pyr1治疗进行慢性LIMK抑制可恢复正常的树突棘密度，并改善长时程增强，这两者在这些小鼠中均发生改变。Pyr1治疗改善了突触可塑性，还减少了MAP6基因敲除小鼠的社交退缩以及抑郁/焦虑样行为。总体而言，本研究结果验证了以下假设：调节LIMK活性可能代表一种治疗神经精神疾病的新策略。
