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Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome

Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is...

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Autores principales: Lysenko, Larisa V., Kim, Jeesun, Henry, Cassandra, Tyrtyshnaia, Anna, Kohnz, Rebecca A., Madamba, Francisco, Simon, Gabriel M., Kleschevnikova, Natalia E., Nomura, Daniel K., Ezekowitz, R . Alan B., Kleschevnikov, Alexander M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256450/
https://www.ncbi.nlm.nih.gov/pubmed/25474204
http://dx.doi.org/10.1371/journal.pone.0114521
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author Lysenko, Larisa V.
Kim, Jeesun
Henry, Cassandra
Tyrtyshnaia, Anna
Kohnz, Rebecca A.
Madamba, Francisco
Simon, Gabriel M.
Kleschevnikova, Natalia E.
Nomura, Daniel K.
Ezekowitz, R . Alan B.
Kleschevnikov, Alexander M.
author_facet Lysenko, Larisa V.
Kim, Jeesun
Henry, Cassandra
Tyrtyshnaia, Anna
Kohnz, Rebecca A.
Madamba, Francisco
Simon, Gabriel M.
Kleschevnikova, Natalia E.
Nomura, Daniel K.
Ezekowitz, R . Alan B.
Kleschevnikov, Alexander M.
author_sort Lysenko, Larisa V.
collection PubMed
description Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS.
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spelling pubmed-42564502014-12-11 Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome Lysenko, Larisa V. Kim, Jeesun Henry, Cassandra Tyrtyshnaia, Anna Kohnz, Rebecca A. Madamba, Francisco Simon, Gabriel M. Kleschevnikova, Natalia E. Nomura, Daniel K. Ezekowitz, R . Alan B. Kleschevnikov, Alexander M. PLoS One Research Article Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS. Public Library of Science 2014-12-04 /pmc/articles/PMC4256450/ /pubmed/25474204 http://dx.doi.org/10.1371/journal.pone.0114521 Text en © 2014 Lysenko et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lysenko, Larisa V.
Kim, Jeesun
Henry, Cassandra
Tyrtyshnaia, Anna
Kohnz, Rebecca A.
Madamba, Francisco
Simon, Gabriel M.
Kleschevnikova, Natalia E.
Nomura, Daniel K.
Ezekowitz, R . Alan B.
Kleschevnikov, Alexander M.
Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome
title Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome
title_full Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome
title_fullStr Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome
title_full_unstemmed Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome
title_short Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome
title_sort monoacylglycerol lipase inhibitor jzl184 improves behavior and neural properties in ts65dn mice, a model of down syndrome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256450/
https://www.ncbi.nlm.nih.gov/pubmed/25474204
http://dx.doi.org/10.1371/journal.pone.0114521
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