Frontiers in Pharmacology (Mar 2021)

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

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

DOI
https://doi.org/10.3389/fphar.2021.627995
Journal volume & issue
Vol. 12

Abstract

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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.

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