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

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Diacylglycerol Lipase-Alpha Regulates Hippocampal-Dependent Learning and Memory Processes in Mice This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Behavioral/Cognitive Diacylglycerol lipase-alpha regulates hippocampal-dependent learning and memory processes in mice Lesley D Schurman1, Moriah C Carper1, Lauren V Moncayo1, Daisuke Ogasawara2, Karen Richardson1, Laikang Yu3, Xiaojie Liu3, Justin L. Poklis1, Qing-Song Liu3, Benjamin F Cravatt2 and Aron H Lichtman1,4 1Department of Pharmacology and Toxicology, Virginia Commonwealth University, 23298 2Department of Molecular Medicine, The Scripps Research Institute, 92037 3Department of Pharmacology and Toxicology, Medical College of Wisconsin, 53226 4Department of Medicinal Chemistry, Virginia Commonwealth University https://doi.org/10.1523/JNEUROSCI.1353-18.2019 Received: 27 May 2018 Revised: 24 April 2019 Accepted: 11 May 2019 Published: 24 May 2019 Author contributions: L.D.S., Q.-S.L., B.F.C., and A.H.L. designed research; L.D.S., M.C., L.V.M., K.R., L.Y., X.L., J.L.P., and Q.-S.L. performed research; L.D.S. and Q.-S.L. analyzed data; L.D.S. wrote the first draft of the paper; L.D.S., J.L.P., and Q.-S.L. wrote the paper; D.O. and B.F.C. contributed unpublished reagents/analytic tools; Q.-S.L., B.F.C., and A.H.L. edited the paper. Conflict of Interest: The authors declare no competing financial interests. This work was supported by the National Institutes of Health (NIH) [Grant NS093990 and DA039942] (to AHL), [Grant 1F31NS095628-01A1] (to LDS), [Grant DA035217] (to QSL), [Grant DA033760] (to BC), and Center grant [P30DA033934]. Start-up funds from the VCU School of Pharmacy also supported this work. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Corresponding Author: Aron H. Lichtman, Department of Pharmacology and Toxicology and Department of Medicinal Chemistry, Virginia Commonwealth University, 23298, USA. E-mail: [email protected] Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.1353-18.2019 Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2019 the authors DAGL-α regulates spatial memory 1 Diacylglycerol lipase-alpha regulates hippocampal-dependent learning and memory processes 2 in mice 3 4 Lesley D Schurman1, Moriah C Carper1, Lauren V Moncayo1, Daisuke Ogasawara2, Karen 5 Richardson1, Laikang Yu3, Xiaojie Liu3, Justin L. Poklis1, Qing-Song Liu3, Benjamin F Cravatt2, 6 and Aron H Lichtman1,4 7 1Department of Pharmacology and Toxicology, Virginia Commonwealth University, 23298, 8 2Department of Molecular Medicine, The Scripps Research Institute, 92037, 9 3Department of Pharmacology and Toxicology, Medical College of Wisconsin, 53226, 10 4Department of Medicinal Chemistry, Virginia Commonwealth University, 23298. 11 12 Number: Pages 38, Figures 10 13 Number of words: Abstract 235, Introduction 650, Discussion 1500 14 Key Words: Diacylglycerol lipase-alpha, spatial memory, long-term potentiation, 15 endocannabinoid, 2-AG, hippocampus. 16 Corresponding Author: Aron H. Lichtman, Department of Pharmacology and Toxicology and 17 Department of Medicinal Chemistry, Virginia Commonwealth University, 23298, USA. E-mail: 18 [email protected]. 19 Conflict of Interest: The authors declare no competing financial interests. 20 Acknowledgements: This work was supported by the National Institutes of Health (NIH) [Grant 21 NS093990 and DA039942] (to AHL), [Grant 1F31NS095628-01A1] (to LDS), [Grant DA035217] 22 (to QSL), [Grant DA033760] (to BC), and Center grant [P30DA033934]. Start-up funds from the 23 VCU School of Pharmacy also supported this work. The content is solely the responsibility of 24 the authors and does not necessarily represent the official views of the NIH. 25 Author Contributions: LDS, QSL, and AHL designed research; LDS, MCC, LVM, DO, KR, LY, 26 XL and JLP performed research; DO and BFC contributed unpublished reagents/analytic tools; 27 LDS analyzed data; and LDS and AHL wrote the paper. 1 DAGL-α regulates spatial memory 28 Abstract 29 Diacylglycerol lipase-α (DAGL-α), the principal biosynthetic enzyme of the endogenous 30 cannabinoid 2-arachidonylglycerol (2-AG) on neurons, plays a key role in CB1 receptor- 31 mediated synaptic plasticity and hippocampal neurogenesis, but its contribution to global 32 hippocampal-mediated processes remains unknown. Thus, the present study examines the role 33 that DAGL-α plays on long-term potentiation (LTP) in hippocampus, as well as in hippocampal- 34 dependent spatial learning and memory tasks, and on the production of endocannabinoid and 35 related lipids through the use of complementary pharmacologic and genetic approaches to 36 disrupt this enzyme in male mice. Here we show that DAGL-α gene deletion or pharmacological 37 inhibition disrupts LTP in CA1 of the hippocampus, but elicits varying magnitudes of behavioral 38 learning and memory deficits in mice. In particular, DAGL-α-/- mice display profound impairments 39 in the Object Location assay and Morris water maze (MWM) acquisition engaging in non-spatial 40 search strategies. In contrast, wild type mice administered the DAGL-α inhibitor DO34 show 41 delays in MWM acquisition and reversal learning, but no deficits in expression, extinction, 42 forgetting, or perseveration processes in this task, as well as no impairment in Object Location. 43 The deficits in synaptic plasticity and MWM performance occur in concert with decreased 2-AG 44 and its major lipid metabolite (arachidonic acid), but increases of a 2-AG diacylglycerol 45 precursor in hippocampus, prefrontal cortex, striatum, and cerebellum. These novel behavioral 46 and electrophysiological results implicate a direct and perhaps selective role of DAGL-α in the 47 integration of new spatial information. 2 DAGL-α regulates spatial memory 48 Significance Statement 49 Here we show that genetic deletion or pharmacologic inhibition of diacylglycerol lipase-α 50 (DAGL-α) impairs hippocampal CA1 LTP, differentially disrupts spatial learning and memory 51 performance in Morris water maze (MWM) and Object Location tasks, and alters brain levels of 52 endocannabinoids and related lipids. Whereas DAGL-α-/- mice exhibit profound phenotypic 53 spatial memory deficits, a DAGL inhibitor selectively impairs the integration of new information 54 in MWM acquisition and reversal tasks, but not memory processes of expression, extinction, 55 forgetting, or perseveration, and does not affect performance in the Objection Location task. 56 The findings that constitutive or short-term DAGL-α disruption impair learning and memory at 57 electrophysiological and selective in vivo levels implicate this enzyme as playing a key role in 58 the integration of new spatial information. 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 3 DAGL-α regulates spatial memory 74 Introduction 75 A growing body of evidence implicates the importance of 2-arachidonoyl glycerol (2-AG), the 76 most highly expressed endogenous cannabinoid in brain, in regulating learning and memory. 77 Diacylglycerol lipase (DAGL) forms 2-AG through the hydrolysis of diacylglycerols (Chau and 78 Tai, 1981; Okazaki et al., 1981) and exists as two distinct biosynthetic enzymes, DAGL-α and 79 DAGL-β (Bisogno et al., 2003b) that are expressed on distinct cell types, as well as in brain 80 areas important for learning and memory (Katona et al., 2006; Lafourcade et al., 2007). Within 81 the central nervous system, DAGL-β is highly expressed on microglia, while DAGL-α, expressed 82 on synapse-rich plasma membranes of dendritic spines (Yoshida et al., 2006), serves as the 83 principal synthetic enzyme of 2-AG on neurons (Viader et al., 2015). 84 DAGL-α modulates neurotransmission through distinct processes of neurogenesis and 85 endocannabinoid-mediated short-term synaptic plasticity, implicating it in learning and memory 86 processes. Adult neurogenesis represents a form of cellular plasticity in the developed brain. 87 Two prominent brain areas showing adult neurogenesis, the subventricular zone and the 88 hippocampus, that express high levels of DAGL-α (Goncalves et al., 2008) undergo marked 89 reductions in the proliferation of neuronal progenitor cells in DAGL-α-/- mice (Gao et al., 2010). 90 Similarly, the non-selective DAGL inhibitors RHC80267 and tetrahydrolipstatin reduce 91 proliferation of neuronal progenitor cells in the subventricular zone (Goncalves et al., 2008). 92 DAGL-α also plays an essential role in endocannabinoid-mediated retrograde synaptic 93 suppression in which 2-AG synthesized at post-synaptic terminals acts as a retrograde 94 messenger to activate the pre-synaptic cannabinoid receptor type 1 (CB1), which inhibits 95 synaptic transmission. Tanimura et al. (2010) reported that deletion of DAGL-α, but not DAGL-β, 96 annihilated two forms of endocannabinoid-mediated short-term synaptic plasticity, 97 depolarization-induced suppression of excitation (DSE) and inhibition (DSI) in hippocampus, 98 striatum, and cerebellum. Similarly, Gao et al. (2010) replicated these findings in hippocampus, 99 and Yoshino et al. (2011) reported that DAGL-α plays a necessary role in DSI in prefrontal 4 DAGL-α regulates spatial memory 100 cortex (PFC). Furthermore, the DAGL inhibitor DO34 blocked DSE in cerebellar slices and DSI 101 in hippocampal slices in a concentration dependent manner (Ogasawara
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