Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome
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{"title"=>"Monoacylglycerol lipase inhibitor JZL184 improves behavior and neural properties in Ts65Dn mice, a model of down syndrome", "type"=>"journal", "authors"=>[{"first_name"=>"Larisa V.", "last_name"=>"Lysenko", "scopus_author_id"=>"56439239700"}, {"first_name"=>"Jeesun", "last_name"=>"Kim", "scopus_author_id"=>"56438241300"}, {"first_name"=>"Cassandra", "last_name"=>"Henry", "scopus_author_id"=>"56438763400"}, {"first_name"=>"Anna", "last_name"=>"Tyrtyshnaia", "scopus_author_id"=>"56440040200"}, {"first_name"=>"Rebecca A.", "last_name"=>"Kohnz", "scopus_author_id"=>"37034225200"}, {"first_name"=>"Francisco", "last_name"=>"Madamba", "scopus_author_id"=>"56440086700"}, {"first_name"=>"Gabriel M.", "last_name"=>"Simon", "scopus_author_id"=>"57197293839"}, {"first_name"=>"Natalia E.", "last_name"=>"Kleschevnikova", "scopus_author_id"=>"56440112200"}, {"first_name"=>"Daniel K.", "last_name"=>"Nomura", "scopus_author_id"=>"6603891118"}, {"first_name"=>"R. Alan B.", "last_name"=>"Ezekowitz", "scopus_author_id"=>"57198138935"}, {"first_name"=>"Alexander M.", "last_name"=>"Kleschevnikov", "scopus_author_id"=>"6602826261"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84915752782", "pmid"=>"25474204", "sgr"=>"84915752782", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0114521", "issn"=>"19326203", "pui"=>"600684516"}, "id"=>"255d2a77-f578-30f6-a647-6b7ec4dffe23", "abstract"=>"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.", "link"=>"http://www.mendeley.com/research/monoacylglycerol-lipase-inhibitor-jzl184-improves-behavior-neural-properties-ts65dn-mice-model-down", "reader_count"=>33, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>2, "Student > Master"=>3, "Other"=>3, "Student > Bachelor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>2, "Student > Master"=>3, "Other"=>3, "Student > Bachelor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>9, "Medicine and Dentistry"=>2, "Neuroscience"=>6, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>2, "Psychology"=>3, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Neuroscience"=>{"Neuroscience"=>6}, "Chemistry"=>{"Chemistry"=>2}, "Psychology"=>{"Psychology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>5}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Spain"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1821483"], "description"=>"<p>A: Levels of Aβ40 were significantly increased in the vehicle-treated Ts65Dn vs. 2N mice. JZL184-treatment reduced the levels of Aβ40 in both Ts65Dn and 2N samples. B: Levels of Aβ42 were also greater in Ts65Dn vs 2N samples and were reduced by the JZL184-treatment.</p>", "links"=>[], "tags"=>["bace", "Ts 65Dn Mice", "Monoacylglycerol Lipase Inhibitor JZL 184", "synaptic", "app", "2 N animals", "brain functions", "ltp", "ds", "pgf", "pgd", "pge", "2 N mice", "ad", "PGJ 2. Enhanced", "Syndrome Genetic alterations", "MAGL inhibition"], "article_id"=>1260129, "categories"=>["Biological Sciences"], "users"=>["Larisa V. Lysenko", "Jeesun Kim", "Cassandra Henry", "Anna Tyrtyshnaia", "Rebecca A. Kohnz", "Francisco Madamba", "Gabriel M. Simon", "Natalia E. Kleschevnikova", "Daniel K. Nomura", "R . Alan B. Ezekowitz", "Alexander M. Kleschevnikov"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114521.g006", "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Levels_of_A_946_species_in_brain_samples_of_mice_treated_with_JZL184_or_vehicle_/1260129", "title"=>"Levels of Aβ species in brain samples of mice treated with JZL184 or vehicle.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:05:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1821484"], "description"=>"<p>A –C: Examples of Western blots for between-group comparison of 2N Veh vs. Ts Veh, 2N Veh vs. 2N JZL, and Ts Veh vs. Ts JZL. D –F: Quantification of the data. Levels of App were increased, while the levels of BACE1 were not altered in the vehicle-treated Ts65Dn vs. 2N brain (A, D). Treatment with JZL184 had no effect on the expression levels of these proteins in either 2N (B, E) or Ts65Dn (C, F).</p>", "links"=>[], "tags"=>["bace", "Ts 65Dn Mice", "Monoacylglycerol Lipase Inhibitor JZL 184", "synaptic", "app", "2 N animals", "brain functions", "ltp", "ds", "pgf", "pgd", "pge", "2 N mice", "ad", "PGJ 2. Enhanced", "Syndrome Genetic alterations", "MAGL inhibition"], "article_id"=>1260130, "categories"=>["Biological Sciences"], "users"=>["Larisa V. Lysenko", "Jeesun Kim", "Cassandra Henry", "Anna Tyrtyshnaia", "Rebecca A. Kohnz", "Francisco Madamba", "Gabriel M. Simon", "Natalia E. Kleschevnikova", "Daniel K. Nomura", "R . Alan B. Ezekowitz", "Alexander M. Kleschevnikov"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114521.g007", "stats"=>{"downloads"=>1, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Levels_of_proteins_/1260130", "title"=>"Levels of proteins.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:05:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1821485"], "description"=>"<p>The values are given in percents of the ‘2N Veh’ group.</p>a)<p>p<0.001. Significant difference vs. ‘2N Veh’ group.</p>b)<p>p<0.001. Significant difference vs. ‘Ts65Dn Veh’ group.</p><p>Effect of chronic JZL184 treatment on the brain levels of endocannabinoids and their metabolites.</p>", "links"=>[], "tags"=>["bace", "Ts 65Dn Mice", "Monoacylglycerol Lipase Inhibitor JZL 184", "synaptic", "app", "2 N animals", "brain functions", "ltp", "ds", "pgf", "pgd", "pge", "2 N mice", "ad", "PGJ 2. Enhanced", "Syndrome Genetic alterations", "MAGL inhibition"], "article_id"=>1260131, "categories"=>["Biological Sciences"], "users"=>["Larisa V. Lysenko", "Jeesun Kim", "Cassandra Henry", "Anna Tyrtyshnaia", "Rebecca A. Kohnz", "Francisco Madamba", "Gabriel M. Simon", "Natalia E. Kleschevnikova", "Daniel K. Nomura", "R . Alan B. Ezekowitz", "Alexander M. Kleschevnikov"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114521.t001", "stats"=>{"downloads"=>1, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_chronic_JZL184_treatment_on_the_brain_levels_of_endocannabinoids_and_their_metabolites_/1260131", "title"=>"Effect of chronic JZL184 treatment on the brain levels of endocannabinoids and their metabolites.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-12-04 03:05:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1821507", "https://ndownloader.figshare.com/files/1821508", "https://ndownloader.figshare.com/files/1821509"], "description"=>"<div><p>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.</p></div>", "links"=>[], "tags"=>["bace", "Ts 65Dn Mice", "Monoacylglycerol Lipase Inhibitor JZL 184", "synaptic", "app", "2 N animals", "brain functions", "ltp", "ds", "pgf", "pgd", "pge", "2 N mice", "ad", "PGJ 2. Enhanced", "Syndrome Genetic alterations", "MAGL inhibition"], "article_id"=>1260141, "categories"=>["Biological Sciences"], "users"=>["Larisa V. Lysenko", "Jeesun Kim", "Cassandra Henry", "Anna Tyrtyshnaia", "Rebecca A. Kohnz", "Francisco Madamba", "Gabriel M. Simon", "Natalia E. Kleschevnikova", "Daniel K. Nomura", "R . Alan B. Ezekowitz", "Alexander M. Kleschevnikov"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0114521.s001", "https://dx.doi.org/10.1371/journal.pone.0114521.s002", "https://dx.doi.org/10.1371/journal.pone.0114521.s003"], "stats"=>{"downloads"=>12, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Monoacylglycerol_Lipase_Inhibitor_JZL184_Improves_Behavior_and_Neural_Properties_in_Ts65Dn_Mice_a_Model_of_Down_Syndrome_/1260141", "title"=>"Monoacylglycerol Lipase Inhibitor JZL184 Improves Behavior and Neural Properties in Ts65Dn Mice, a Model of Down Syndrome", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-12-04 03:05:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1821473"], "description"=>"<p>In the vehicle-treated animals, locomotor activity was significantly increased in Ts65Dn vs. 2N mice. This can be seen from the increased ambulatory distance (A) and ambulatory time (B) and decreased resting time (C) of Ts Veh vs. 2N Veh group. Treatment with JZL184 (8 mg/kg) restored these locomotion parameters to control levels. In addition, Ts65Dn mice exhibited increased thigmotactic behavior which can be seen from an increased percentage of ambulatory distance (D), ambulatory time (E), and resting time (F) on the arena periphery. JZL184 treatment had no effect on these parameters.</p>", "links"=>[], "tags"=>["bace", "Ts 65Dn Mice", "Monoacylglycerol Lipase Inhibitor JZL 184", "synaptic", "app", "2 N animals", "brain functions", "ltp", "ds", "pgf", "pgd", "pge", "2 N mice", "ad", "PGJ 2. Enhanced", "Syndrome Genetic alterations", "MAGL inhibition"], "article_id"=>1260119, "categories"=>["Biological Sciences"], "users"=>["Larisa V. Lysenko", "Jeesun Kim", "Cassandra Henry", "Anna Tyrtyshnaia", "Rebecca A. Kohnz", "Francisco Madamba", "Gabriel M. Simon", "Natalia E. Kleschevnikova", "Daniel K. Nomura", "R . Alan B. Ezekowitz", "Alexander M. Kleschevnikov"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114521.g001", "stats"=>{"downloads"=>2, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_ZL184_treatment_on_locomotor_activity_A_C_and_thigmotactic_behavior_D_F_/1260119", "title"=>"Effects of ZL184-treatment on locomotor activity (A-C) and thigmotactic behavior (D-F).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:05:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1821474"], "description"=>"<p>A. The baseline rate of spontaneous alternations in Y-maze was lower in the vehicle-treated Ts65Dn vs. 2N mice, reflecting an impairment of working memory. JZL184-treatment had no effect on the performance of both 2N and Ts65Dn mice suggesting no effect on working memory. B. The number of ‘arm entries’ during the Y-maze test was greater in vehicle-treated Ts65Dn vs. 2N mice reflecting increased locomotion of Ts65Dn mice. JZL184-treatment reduced this parameter to the levels seen in 2N animals.</p>", "links"=>[], "tags"=>["bace", "Ts 65Dn Mice", "Monoacylglycerol Lipase Inhibitor JZL 184", "synaptic", "app", "2 N animals", "brain functions", "ltp", "ds", "pgf", "pgd", "pge", "2 N mice", "ad", "PGJ 2. Enhanced", "Syndrome Genetic alterations", "MAGL inhibition"], "article_id"=>1260120, "categories"=>["Biological Sciences"], "users"=>["Larisa V. Lysenko", "Jeesun Kim", "Cassandra Henry", "Anna Tyrtyshnaia", "Rebecca A. Kohnz", "Francisco Madamba", "Gabriel M. Simon", "Natalia E. Kleschevnikova", "Daniel K. Nomura", "R . Alan B. Ezekowitz", "Alexander M. Kleschevnikov"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114521.g002", "stats"=>{"downloads"=>2, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Working_memory_performance_in_Y_maze_/1260120", "title"=>"Working memory: performance in Y-maze.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:05:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1821477"], "description"=>"<p>A: Time spent investigating objects during acquisition. There was no difference between the groups. B: Testing phase. Left: Time spent investigating objects during testing. Vehicle-treated Ts65Dn mice spent less time investigating the objects than their littermate 2N controls. There was no such difference in the JZL-treated groups. Right: Discrimination index was smaller in both vehicle- and JZL-treated Ts65Dn vs. 2N groups. Thus, short-term memory was not affected by the JZL184-treatment.</p>", "links"=>[], "tags"=>["bace", "Ts 65Dn Mice", "Monoacylglycerol Lipase Inhibitor JZL 184", "synaptic", "app", "2 N animals", "brain functions", "ltp", "ds", "pgf", "pgd", "pge", "2 N mice", "ad", "PGJ 2. Enhanced", "Syndrome Genetic alterations", "MAGL inhibition"], "article_id"=>1260123, "categories"=>["Biological Sciences"], "users"=>["Larisa V. Lysenko", "Jeesun Kim", "Cassandra Henry", "Anna Tyrtyshnaia", "Rebecca A. Kohnz", "Francisco Madamba", "Gabriel M. Simon", "Natalia E. Kleschevnikova", "Daniel K. Nomura", "R . Alan B. Ezekowitz", "Alexander M. Kleschevnikov"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114521.g003", "stats"=>{"downloads"=>3, "page_views"=>25, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Short_term_memory_Novel_place_recognition_with_the_retention_period_of_10_min_/1260123", "title"=>"Short-term memory: Novel place recognition with the retention period of 10 min.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:05:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1821478"], "description"=>"<p>A: Time of object exploration during acquisition. There was no difference between the groups, and no effect of JZL184-treatment on the exploration time. B: Testing phase. Left: Time of object exploration during testing was smaller in vehicle-treated Ts65Dn vs. 2N mice. There was no such difference between the JZL184-treated Ts65Dn and 2N groups. Right: Discrimination index was smaller in the vehicle-treated Ts65Dn vs. 2N mice. JZL184-treatment significantly increased the discrimination index in Ts65Dn mice, but had no effect on the performance of their 2N littermates.</p>", "links"=>[], "tags"=>["bace", "Ts 65Dn Mice", "Monoacylglycerol Lipase Inhibitor JZL 184", "synaptic", "app", "2 N animals", "brain functions", "ltp", "ds", "pgf", "pgd", "pge", "2 N mice", "ad", "PGJ 2. Enhanced", "Syndrome Genetic alterations", "MAGL inhibition"], "article_id"=>1260124, "categories"=>["Biological Sciences"], "users"=>["Larisa V. Lysenko", "Jeesun Kim", "Cassandra Henry", "Anna Tyrtyshnaia", "Rebecca A. Kohnz", "Francisco Madamba", "Gabriel M. Simon", "Natalia E. Kleschevnikova", "Daniel K. Nomura", "R . Alan B. Ezekowitz", "Alexander M. Kleschevnikov"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114521.g004", "stats"=>{"downloads"=>6, "page_views"=>66, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Long_term_memory_Novel_object_recognition_with_the_retention_period_of_24_hours_/1260124", "title"=>"Long-term memory: Novel object recognition with the retention period of 24 hours.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:05:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1821481"], "description"=>"<p>A: In the vehicle-treated animals, LTP was smaller in Ts65Dn vs. 2N slices. Scale bars: 1 mV; 2 ms. B: In the JZL184-treated mice, there was no difference between the Ts65Dn vs. 2N slices. C: Quantification of the data. JZL184-treatment increased LTP in Ts65Dn mice.</p>", "links"=>[], "tags"=>["bace", "Ts 65Dn Mice", "Monoacylglycerol Lipase Inhibitor JZL 184", "synaptic", "app", "2 N animals", "brain functions", "ltp", "ds", "pgf", "pgd", "pge", "2 N mice", "ad", "PGJ 2. Enhanced", "Syndrome Genetic alterations", "MAGL inhibition"], "article_id"=>1260127, "categories"=>["Biological Sciences"], "users"=>["Larisa V. Lysenko", "Jeesun Kim", "Cassandra Henry", "Anna Tyrtyshnaia", "Rebecca A. Kohnz", "Francisco Madamba", "Gabriel M. Simon", "Natalia E. Kleschevnikova", "Daniel K. Nomura", "R . Alan B. Ezekowitz", "Alexander M. Kleschevnikov"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0114521.g005", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Long_term_potentiation_in_the_CA1_region_of_hippocampal_slices_of_Ts65Dn_and_2N_mice_/1260127", "title"=>"Long-term potentiation in the CA1 region of hippocampal slices of Ts65Dn and 2N mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-12-04 03:05:52"}

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