title: Monoacylglycerol lipase inhibitor JZL184 improves behavior and neural properties in Ts65Dn mice, a model of down syndrome.
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.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, United States of America.
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Lysenko
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, United States of America.
authors.forename: Jeesun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Abide Therapeutics, Inc., San Diego, CA, United States of America.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Henry
authors.affiliation: School of Biomedicine, Far Eastern Federal University, Sukhanova 8, Vladivostok, Russian Federation.
authors.forename: Anna
authors.initials: A
authors.lastname: Tyrtyshnaia
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, United States of America.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Kohnz
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, United States of America.
authors.forename: Francisco
authors.initials: F
authors.lastname: Madamba
authors.affiliation: Abide Therapeutics, Inc., San Diego, CA, United States of America.
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Simon
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, United States of America.
authors.forename: Natalia E
authors.initials: NE
authors.lastname: Kleschevnikova
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, United States of America.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: Abide Therapeutics, Inc., San Diego, CA, United States of America.
authors.forename: R Alan B
authors.initials: RA
authors.lastname: Ezekowitz
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, CA, United States of America.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Kleschevnikov
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000523:psychology; D004353:Drug Evaluation, Preclinical; D063388:Endocannabinoids / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D008570:Memory, Short-Term / Q000187:drug effects; D008822:Mice, Transgenic; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D021641:Recognition, Psychology
chemical_list: D014151:Anti-Anxiety Agents; D052117:Benzodioxoles; D063388:Endocannabinoids; C534333:JZL 184; D010880:Piperidines; D008994:Monoacylglycerol Lipases