Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus

Hashimotodani, Yuki; Ohno‐Shosaku, Takako; Kano, Masanobu

doi:10.1523/jneurosci.4159-06.2007

Cited by 167 publications

(181 citation statements)

References 48 publications

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“…Among the several eCBs that have been identified in the brain, 2-arachidonoyl glycerol (2-AG), is one of the most abundant Kogan and Mechoulam, 2006;Piomelli, 2003), and reportedly mediates DSI in cerebellum, striatum (Szabo et al, 2006) and presumably in hippocampus as well (Hashimotodani et al, 2007;Kim and Alger, 2004;Makara et al, 2005). The main enzyme responsible for 2-AG production, diacylglycerol lipase (DGL), is highly expressed in the SGL (Katona et al, 2006), suggesting that 2-AG may also be involved in DSE at the MCF-DGC synapse.…”

Section: Resultsmentioning

confidence: 99%

Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus

Chiu

Castillo

2008

Neuropharmacology

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SummaryEndocannabinoids (eCBs) mediate transient and long-lasting synaptic plasticity in several brain structures. In the dentate gyrus, activation of the type 1 cannabinoid receptor (CB1R) by exogenous ligands reportedly depresses excitatory synaptic transmission. However, direct evidence of eCB signaling at excitatory synapses in this region has been lacking. Here, we demonstrate that eCB release can be induced by a brief postsynaptic depolarization of dentate granule cells (DGCs), which potently and transiently suppresses glutamatergic inputs from mossy cell interneurons (MCs) but not from entorhinal cortex via the lateral and medial perforant paths. This input-specific depolarizationinduced suppression of excitation (DSE) is calcium-dependent and can be modulated by agonists of cholinergic and group I metabotropic glutamate receptors. Inhibiting the synthesis of 2-arachidonoyl glycerol (2-AG), one of the most abundant eCBs in the brain, by diacyglycerol lipase (DGL) does not abolish DSE. Moreover, preventing the breakdown of anandamide, the other main eCB, does not potentiate DSE. Thus, eCB signaling underlying DSE in the dentate does not require DGL activity and is unlikely to be mediated by anandamide. Finally, we find that manipulations known to induce eCB-LTD at other central synapses do not trigger LTD at MCF-DGC synapses.

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Section: Resultsmentioning

confidence: 99%

Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus

Chiu

Castillo

2008

Neuropharmacology

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“…As a major degrading enzyme, MGL restricts the spread of 2-AG both spatially and temporally (Hashimotodani et al, 2007a;Pan et al, 2009). We next examined cellular expression and subcellular distribution of MGL.…”

Section: Mgl Is Lacking In Mc-gc Synapsesmentioning

confidence: 99%

“…2-Arachidonoylglycerol (2-AG) is the major eCB in the brain (Mechoulam et al, 1995;Sugiura et al, 1995;Stella et al, 1997) and is synthesized by sn-1 diacylglycerol lipase ␣ (DGL␣) in postsynaptic elements (Bisogno et al, 2003;Katona et al, 2006;Yoshida et al, 2006;Gao et al, 2010;Tanimura et al, 2010). 2-AG is degraded mainly by monoacylglycerol lipase (MGL) (Dinh et al, 2002;Blankman et al, 2007;Schlosburg et al, 2010), which is expressed in presynaptic terminals (Gulyas et al, 2004) and regulates the magnitude and time course of 2-AG-mediated retrograde signaling (Hashimotodani et al, 2007a;Pan et al, 2009). These molecular components are well orchestrated at individual synapses with some variations according to neuronal and synaptic organization (Kano et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Molecular and Morphological Configuration for 2-Arachidonoylglycerol-Mediated Retrograde Signaling at Mossy Cell–Granule Cell Synapses in the Dentate Gyrus

Uchigashima¹,

Yamazaki²,

Yamasaki³

et al. 2011

J. Neurosci.

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2-Arachidonoylglycerol (2-AG) is the endocannabinoid that mediates retrograde suppression of neurotransmission in the brain. In the present study, we investigated the 2-AG signaling system at mossy cell (MC)-granule cell (GC) synapses in the mouse dentate gyrus, an excitatory recurrent circuit where endocannabinoids are thought to suppress epileptogenesis. First, we showed by electrophysiology that 2-AG produced by diacylglycerol lipase ␣ (DGL␣) mediated both depolarization-induced suppression of excitation and its enhancement by group I metabotropic glutamate receptor activation at MC-GC synapses, as they were abolished in DGL␣-knock-out mice. Immunohistochemistry revealed that DGL␣ was enriched in the neck portion of GC spines forming synapses with MC terminals, whereas cannabinoid CB 1 receptors accumulated in the terminal portion of MC axons. On the other hand, the major 2-AG-degrading enzyme, monoacylglycerol lipase (MGL), was absent at MC-GC synapses but was expressed in astrocytes and some inhibitory terminals. Serial electron microscopy clarified that a given GC spine was innervated by a single MC terminal and also contacted nonsynaptically by other MC terminals making synapses with other GC spines in the neighborhood. MGL-expressing elements, however, poorly covered GC spines, amounting to 17% of the total surface of GC spines by astrocytes and 4% by inhibitory terminals. Our findings provide a basis for 2-AG-mediated retrograde suppression of MC-GC synaptic transmission and also suggest that 2-AG released from activated GC spines is readily accessible to nearby MC-GC synapses by escaping from enzymatic degradation. This molecular-anatomical configuration will contribute to adjust network activity in the dentate gyrus after enhanced excitation.

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“…Importantly, variations in this basic scheme account for numerous forms of short-and long-term synaptic plasticity and experiencedependent modifications of neuronal activity in the CNS from the spinal cord to the neocortex (Chevaleyre et al, 2006). The major endocannabinoid responsible for retrograde synaptic communication is proposed to be 2-arachidonoylglycerol (2-AG) (Kim and Alger, 2004;Makara et al, 2005;Hashimotodani et al, 2007). In contrast to the physiological role of 2-AG, the cellular mechanisms of endogenous signaling pathways mediated by other endocannabinoids remain obscure.…”

Section: Introductionmentioning

confidence: 99%

Enzymatic Machinery for Endocannabinoid Biosynthesis Associated with Calcium Stores in Glutamatergic Axon Terminals

Nyilas¹,

Dudok²,

Urbán³

et al. 2008

J. Neurosci.

105

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Endocannabinoids are regarded as retrograde signaling molecules at various types of synapses throughout the CNS. The lipid derivatives anandamide and 2-arachidonoylglycerol (2-AG) are generally thought to be the key molecular players in this process. Previous anatomical and electrophysiological studies provided compelling evidence that the biosynthetic enzyme of 2-AG is indeed localized in the postsynaptic plasma membrane, whereas its target, the CB 1 cannabinoid receptor, and the enzyme responsible for its inactivation are both found presynaptically. This molecular architecture of 2-AG signaling is a conserved feature of most synapses and supports the retrograde signaling role of 2-AG. Conversely, the molecular and neuroanatomical organization of synaptic anandamide signaling remains largely unknown. In contrast to its predicted role in retrograde signaling, here we show that N-acylphosphatidylethanolaminehydrolyzing phospholipase D (NAPE-PLD), a biosynthetic enzyme of anandamide and its related bioactive congeners, the N-acylethanolamines (NAEs), is concentrated presynaptically in several types of hippocampal excitatory axon terminals. Furthermore, high-resolution quantitative immunogold labeling demonstrates that this calcium-sensitive enzyme is localized predominantly on the intracellular membrane cisternae of axonal calcium stores. Finally, the highest density of NAPE-PLD is found in mossy terminals of granule cells, which do not express CB 1 receptors. Together, these findings suggest that anandamide and related NAEs are also present at glutamatergic synapses, but the sites of their synthesis and action are remarkably different from 2-AG, indicating distinct physiological roles for given endocannabinoids in the regulation of synaptic neurotransmission and plasticity.

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Presynaptic Monoacylglycerol Lipase Activity Determines Basal Endocannabinoid Tone and Terminates Retrograde Endocannabinoid Signaling in the Hippocampus

Cited by 167 publications

References 48 publications

Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus

Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus

Molecular and Morphological Configuration for 2-Arachidonoylglycerol-Mediated Retrograde Signaling at Mossy Cell–Granule Cell Synapses in the Dentate Gyrus

Enzymatic Machinery for Endocannabinoid Biosynthesis Associated with Calcium Stores in Glutamatergic Axon Terminals

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