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Research Articles, Behavioral/Cognitive

Diacylglycerol Lipase-Alpha Regulates Hippocampal-Dependent Learning and Memory Processes in Mice

Lesley D. Schurman, Moriah C. Carper, Lauren V. Moncayo, Daisuke Ogasawara, Karen Richardson, Laikang Yu, Xiaojie Liu, Justin L. Poklis, Qing-Song Liu, Benjamin F. Cravatt and Aron H. Lichtman
Journal of Neuroscience 24 July 2019, 39 (30) 5949-5965; DOI: https://doi.org/10.1523/JNEUROSCI.1353-18.2019
Lesley D. Schurman
1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298,
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Moriah C. Carper
1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298,
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Lauren V. Moncayo
1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298,
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Daisuke Ogasawara
2Department of Molecular Medicine, Scripps Research Institute, La Jolla, California 92037,
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Karen Richardson
1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298,
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Laikang Yu
3Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and
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Xiaojie Liu
3Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and
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Justin L. Poklis
1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298,
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Qing-Song Liu
3Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and
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Benjamin F. Cravatt
2Department of Molecular Medicine, Scripps Research Institute, La Jolla, California 92037,
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Aron H. Lichtman
1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298,
4Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, Virginia 23298
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Abstract

Diacylglycerol lipase-α (DAGL-α), the principal biosynthetic enzyme of the endogenous cannabinoid 2-arachidonylglycerol (2-AG) on neurons, plays a key role in CB1 receptor-mediated synaptic plasticity and hippocampal neurogenesis, but its contribution to global hippocampal-mediated processes remains unknown. Thus, the present study examines the role that DAGL-α plays on LTP in hippocampus, as well as in hippocampal-dependent spatial learning and memory tasks, and on the production of endocannabinoid and related lipids through the use of complementary pharmacologic and genetic approaches to disrupt this enzyme in male mice. Here we show that DAGL-α gene deletion or pharmacological inhibition disrupts LTP in CA1 of the hippocampus but elicits varying magnitudes of behavioral learning and memory deficits in mice. In particular, DAGL-α−/− mice display profound impairments in the Object Location assay and Morris Water Maze (MWM) acquisition engaging in nonspatial search strategies. In contrast, WT mice administered the DAGL-α inhibitor DO34 show delays in MWM acquisition and reversal learning, but no deficits in expression, extinction, forgetting, or perseveration processes in this task, as well as no impairment in Object Location. The deficits in synaptic plasticity and MWM performance occur in concert with decreased 2-AG and its major lipid metabolite (arachidonic acid), but increases of a 2-AG diacylglycerol precursor in hippocampus, PFC, striatum, and cerebellum. These novel behavioral and electrophysiological results implicate a direct and perhaps selective role of DAGL-α in the integration of new spatial information.

SIGNIFICANCE STATEMENT Here we show that genetic deletion or pharmacologic inhibition of diacylglycerol lipase-α (DAGL-α) impairs hippocampal CA1 LTP, differentially disrupts spatial learning and memory performance in Morris water maze (MWM) and Object Location tasks, and alters brain levels of endocannabinoids and related lipids. Whereas DAGL-α−/− mice exhibit profound phenotypic spatial memory deficits, a DAGL inhibitor selectively impairs the integration of new information in MWM acquisition and reversal tasks, but not memory processes of expression, extinction, forgetting, or perseveration, and does not affect performance in the Objection Location task. The findings that constitutive or short-term DAGL-α disruption impairs learning and memory at electrophysiological and selective in vivo levels implicate this enzyme as playing a key role in the integration of new spatial information.

  • 2-arachidonylglycerol
  • diacylglycerol lipase
  • endocannabinoid
  • endogenous cannabinoid
  • LTP
  • Morris water maze
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The Journal of Neuroscience: 39 (30)
Journal of Neuroscience
Vol. 39, Issue 30
24 Jul 2019
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Diacylglycerol Lipase-Alpha Regulates Hippocampal-Dependent Learning and Memory Processes in Mice
Lesley D. Schurman, Moriah C. Carper, Lauren V. Moncayo, Daisuke Ogasawara, Karen Richardson, Laikang Yu, Xiaojie Liu, Justin L. Poklis, Qing-Song Liu, Benjamin F. Cravatt, Aron H. Lichtman
Journal of Neuroscience 24 July 2019, 39 (30) 5949-5965; DOI: 10.1523/JNEUROSCI.1353-18.2019

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Diacylglycerol Lipase-Alpha Regulates Hippocampal-Dependent Learning and Memory Processes in Mice
Lesley D. Schurman, Moriah C. Carper, Lauren V. Moncayo, Daisuke Ogasawara, Karen Richardson, Laikang Yu, Xiaojie Liu, Justin L. Poklis, Qing-Song Liu, Benjamin F. Cravatt, Aron H. Lichtman
Journal of Neuroscience 24 July 2019, 39 (30) 5949-5965; DOI: 10.1523/JNEUROSCI.1353-18.2019
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Keywords

  • 2-arachidonylglycerol
  • diacylglycerol lipase
  • endocannabinoid
  • endogenous cannabinoid
  • LTP
  • Morris water maze

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