Pyr1-Mediated Pharmacological Inhibition of LIM Kinase Restores Synaptic Plasticity and Normal Behavior in a Mouse Model of Schizophrenia

Frontiers in Pharmacology

Chi Hung Nguyen¹  Annie Andrieux³  Eric Denarier³  Laurence Lafanechère⁴  Julie Jonckheere⁵  Alain Buisson⁵  Rebecca Powell⁵  Sylvie Gory-Fauré⁵  Fabien Lanté⁵  Leticia Peris⁵ 

[1] Chimie et Modélisation pour la Biologie du Cancer, Institut Curie, PSL Research University, CNRS UMR9187, Inserm U1196, Orsay, France;Department of Molecular and Cellular Neurosciences, Grenoble Institute Neuroscience, Inserm U1216, Grenoble, France;Health Department, Interdisciplinary Research Institute of Grenoble, CEA, Grenoble, France;Microenvironment, Cell Plasticity and Signaling Department, Institute for Advanced Biosciences, CNRS UMR5309, Inserm U1209, Grenoble, France;Université Grenoble Alpes, Grenoble, France;

关键词: MAP6;    LIM kinase;    actin;    microtubule;    therapeutics;    cytoskeleton;   

DOI  :  10.3389/fphar.2021.627995

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown