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

Sylvie Gory-Fauré,Julie Jonckheere,Eric Denarier,Leticia Peris,Fabien Lanté,Annie Andrieux,Chi Hung Nguyen,Laurence Lafanechère,Rebecca Powell,Alain Buisson

doi:10.3389/fphar.2021.627995

Abstract

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.

Highlights

Our knowledge of the brain defects associated with neuropsychiatric disorders has only started to increase since the start of the second millennium, thanks to the development of new techniques and advances in imagery
MAP6 KO mice were used as a model of schizophrenia and the impact of long-term treatment with Pyr1, a LIM Kinase (LIMK) inhibitor and a modulator of MT/actin dynamic (Prudent et al, 2012), on MAP6 KO mice defects, was analyzed in terms of behavioral, anatomic and physiological parameters
We monitored the levels of phospho-cofilin (p-Cof) and cofilin (Cof) in hippocampal neurons grown for 17 days in vitro and exposed to Pyr1 for 30 min, and compared them to levels measured in control cultures

Summary

Introduction

Our knowledge of the brain defects associated with neuropsychiatric disorders has only started to increase since the start of the second millennium, thanks to the development of new techniques and advances in imagery. Much work initially focused on the function and regulation of actin filaments in dendritic spines, but more recently microtubules (MTs) originating from the dendritic shaft were shown to enter into spines to regulate their activity and morphology (Jaworski et al, 2009; Hotulainen and Hoogenraad, 2010; Kapitein et al, 2010) In accordance with these key roles, synaptic cytoskeletal alterations can lead to cognitive defects with both abnormal neuronal connectivity and defective synaptic plasticity. Few pharmacological regulators of LIMKs have been identified (Prunier et al, 2016; Manetti, 2018), Pyr was found to be highly selective and, in cycling cells, capable of stabilizing MTs and modulating actin dynamics (Prudent et al, 2012)

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