Pyr1-Mediated Pharmacological Inhibition of LIM Kinase Restores Synaptic Plasticity and Normal Behavior in a Mouse Model of Schizophrenia.
LIM kinase
MAP6
actin
cognitive abilities
cytoskeleton
microtubule
therapeutics
Journal
Frontiers in pharmacology
ISSN: 1663-9812
Titre abrégé: Front Pharmacol
Pays: Switzerland
ID NLM: 101548923
Informations de publication
Date de publication:
2021
2021
Historique:
received:
10
11
2020
accepted:
04
02
2021
entrez:
1
4
2021
pubmed:
2
4
2021
medline:
2
4
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33790791
doi: 10.3389/fphar.2021.627995
pii: 627995
pmc: PMC8006432
doi:
Types de publication
Journal Article
Langues
eng
Pagination
627995Informations de copyright
Copyright © 2021 Gory-Fauré, Powell, Jonckheere, Lanté, Denarier, Peris, Nguyen, Buisson, Lafanechère and Andrieux.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Mol Psychiatry. 2015 May;20(5):563-572
pubmed: 25113377
Neuron. 2009 May 28;62(4):479-93
pubmed: 19477151
Eur J Cell Biol. 2008 Sep;87(8-9):649-67
pubmed: 18499298
Nat Commun. 2018 Sep 17;9(1):3775
pubmed: 30224655
Biol Psychiatry. 2015 Jan 1;77(1):52-8
pubmed: 25152434
J Biol Chem. 2005 Jul 15;280(28):26533-42
pubmed: 15897190
Hum Mol Genet. 2012 Oct 15;21(20):4406-18
pubmed: 22798627
Nat Commun. 2015 Jun 03;6:7246
pubmed: 26037503
Pharmacol Ther. 2017 Jul;175:17-27
pubmed: 28232023
Oncotarget. 2017 Jun 20;8(25):41749-41763
pubmed: 28445157
Peptides. 2010 Jul;31(7):1368-73
pubmed: 20417241
Nature. 2014 Feb 13;506(7487):179-84
pubmed: 24463507
Autophagy. 2014;10(12):2324-32
pubmed: 25484074
Sci Rep. 2017 Sep 6;7(1):10681
pubmed: 28878401
J Neurochem. 2012 Apr;121(1):99-114
pubmed: 22146001
Mol Cell Neurosci. 2011 Dec;48(4):359-64
pubmed: 21757008
Biol Psychiatry. 2015 Dec 1;78(11):775-85
pubmed: 25981171
Trends Cell Biol. 1999 Sep;9(9):364-70
pubmed: 10461190
Brain Res. 2000 Jul 7;870(1-2):20-6
pubmed: 10869497
Neuron. 2009 Jan 15;61(1):85-100
pubmed: 19146815
J Cell Biol. 2010 May 17;189(4):619-29
pubmed: 20457765
PLoS One. 2008 Apr 23;3(4):e1997
pubmed: 18431482
Neuron. 2002 Jul 3;35(1):121-33
pubmed: 12123613
Mol Psychiatry. 2015 Sep;20(9):1037-45
pubmed: 26077693
Front Synaptic Neurosci. 2020 Aug 28;12:36
pubmed: 32982715
Neuroscience. 2008 Nov 11;157(1):29-39
pubmed: 18804150
Psychopharmacology (Berl). 2010 Jan;208(1):131-41
pubmed: 19936716
Elife. 2015 Apr 17;4:e06327
pubmed: 25884247
Trends Pharmacol Sci. 2014 Dec;35(12):675-87
pubmed: 25455365
Front Pharmacol. 2020 Apr 30;11:543
pubmed: 32425788
Neurobiol Learn Mem. 2020 Sep;173:107275
pubmed: 32659348
Genes Dev. 2002 Sep 15;16(18):2350-64
pubmed: 12231625
Cancer Res. 2012 Sep 1;72(17):4429-39
pubmed: 22761334
J Neurochem. 2012 Dec;123(6):982-96
pubmed: 23013328
J Biol Chem. 2004 Jul 2;279(27):28531-8
pubmed: 15123709
Ann N Y Acad Sci. 2006 Aug;1074:90-6
pubmed: 17105906
Curr Opin Neurobiol. 2020 Aug;63:9-14
pubmed: 32062144
Behav Brain Res. 2005 Sep 8;163(2):257-64
pubmed: 16046005
Behav Neurosci. 2007 Oct;121(5):826-35
pubmed: 17907815
Cytoskeleton (Hoboken). 2016 Oct;73(10):596-611
pubmed: 27112918
Sci Signal. 2019 Jun 25;12(587):
pubmed: 31239325
Eur J Med Chem. 2018 Jul 15;155:445-458
pubmed: 29908439
J Neurochem. 2010 Dec;115(6):1579-94
pubmed: 20969568
Hum Mol Genet. 2006 Oct 15;15(20):3041-54
pubmed: 16980328
Bioessays. 2004 Feb;26(2):141-50
pubmed: 14745832
Schizophr Bull. 2013 Sep;39(5):969-78
pubmed: 23002183
Biol Psychiatry. 2006 Dec 1;60(11):1224-30
pubmed: 16806091
J Biol Chem. 2014 Oct 24;289(43):30133-43
pubmed: 25225289
Curr Drug Targets CNS Neurol Disord. 2004 Dec;3(6):515-33
pubmed: 15581421
Neural Regen Res. 2016 Jul;11(7):1029-32
pubmed: 27630670
Science. 2003 Aug 8;301(5634):805-9
pubmed: 12907793
Brain Stimul. 2018 Nov - Dec;11(6):1336-1347
pubmed: 30146428
Cancer Res. 2016 Jun 15;76(12):3541-52
pubmed: 27216191
Oncotarget. 2014 Nov 30;5(22):11490-500
pubmed: 25359780
J Biol Chem. 2011 Dec 2;286(48):41466-41478
pubmed: 21953449
Nat Neurosci. 2014 May;17(5):678-85
pubmed: 24657968
Methods Cell Biol. 2010;97:111-32
pubmed: 20719268
Neuron. 2000 Oct;28(1):41-51
pubmed: 11086982
Neuropsychologia. 2006;44(5):679-85
pubmed: 16216290
Neuron. 2013 May 22;78(4):644-57
pubmed: 23719163
Neuron. 2014 Apr 16;82(2):444-59
pubmed: 24742465
Hum Mol Genet. 2003 Jul 1;12(13):1591-608
pubmed: 12812986
J Neurosci. 2008 Dec 3;28(49):13094-105
pubmed: 19052200