Kano M

References (13)

Title : An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum - Lai_2021_Front.Neural.Circuits_15_676891
Author(s) : Lai ESK , Nakayama H , Miyazaki T , Nakazawa T , Tabuchi K , Hashimoto K , Watanabe M , Kano M
Ref : Front Neural Circuits , 15 :676891 , 2021
Abstract : Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10-15 (P10-15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD.
ESTHER : Lai_2021_Front.Neural.Circuits_15_676891
PubMedSearch : Lai_2021_Front.Neural.Circuits_15_676891
PubMedID: 34262438
Gene_locus related to this paper: human-NLGN3

Title : Quantification of plasma exosome is a potential prognostic marker for esophageal squamous cell carcinoma - Matsumoto_2016_Oncol.Rep_36_2535
Author(s) : Matsumoto Y , Kano M , Akutsu Y , Hanari N , Hoshino I , Murakami K , Usui A , Suito H , Takahashi M , Otsuka R , Xin H , Komatsu A , Iida K , Matsubara H
Ref : Oncol Rep , 36 :2535 , 2016
Abstract : Exosomes play important roles in cancer progression. Although its contents (e.g., proteins and microRNAs) have been focused on in cancer research, particularly as potential diagnostic markers, the exosome behavior and methods for exosome quantification remain unclear. In the present study, we analyzed the tumor-derived exosome behavior and assessed the quantification of exosomes in patient plasma as a biomarker for esophageal squamous cell carcinoma (ESCC). A CD63-GFP expressing human ESCC cell line (TE2-CD63-GFP) was made by transfection, and mouse subcutaneous tumor models were established. Fluorescence imaging was performed on tumors and plasma exosomes harvested from mice. GFP-positive small vesicles were confirmed in the plasma obtained from TE2-CD63-GFP tumor-bearing mice. Patient plasma was collected in Chiba University Hospital (n=86). Exosomes were extracted from 100 microl of the plasma and quantified by acetylcholinesterase (AChE) activity. The relationship between exosome quantification and the patient clinical characteristics was assessed. The quantification of exosomes isolated from the patient plasma revealed that esophageal cancer patients (n=66) expressed higher exosome levels than non-malignant patients (n=20) (P=0.0002). Although there was no correlation between the tumor progression and the exosome levels, exosome number was the independent prognostic marker and low levels of exosome predicted a poor prognosis (P=0.03). In conclusion, exosome levels may be useful as an independent prognostic factor for ESCC patients.
ESTHER : Matsumoto_2016_Oncol.Rep_36_2535
PubMedSearch : Matsumoto_2016_Oncol.Rep_36_2535
PubMedID: 27599779

Title : Heterogeneous presynaptic distribution of monoacylglycerol lipase, a multipotent regulator of nociceptive circuits in the mouse spinal cord - Horvath_2014_Eur.J.Neurosci_39_419
Author(s) : Horvath E , Woodhams SG , Nyilas R , Henstridge CM , Kano M , Sakimura K , Watanabe M , Katona I
Ref : European Journal of Neuroscience , 39 :419 , 2014
Abstract : Monoacylglycerol lipase (MGL) is a multifunctional serine hydrolase, which terminates anti-nociceptive endocannabinoid signaling and promotes pro-nociceptive prostaglandin signaling. Accordingly, both acute nociception and its sensitization in chronic pain models are prevented by systemic or focal spinal inhibition of MGL activity. Despite its analgesic potential, the neurobiological substrates of beneficial MGL blockade have remained unexplored. Therefore, we examined the regional, cellular and subcellular distribution of MGL in spinal circuits involved in nociceptive processing. All immunohistochemical findings obtained with light, confocal or electron microscopy were validated in MGL-knockout mice. Immunoperoxidase staining revealed a highly concentrated accumulation of MGL in the dorsal horn, especially in superficial layers. Further electron microscopic analysis uncovered that the majority of MGL-immunolabeling is found in axon terminals forming either asymmetric glutamatergic or symmetric gamma-aminobutyric acid/glycinergic synapses in laminae I/IIo. In line with this presynaptic localization, analysis of double-immunofluorescence staining by confocal microscopy showed that MGL colocalizes with neurochemical markers of peptidergic and non-peptidergic nociceptive terminals, and also with markers of local excitatory or inhibitory interneurons. Interestingly, the ratio of MGL-immunolabeling was highest in calcitonin gene-related peptide-positive peptidergic primary afferents, and the staining intensity of nociceptive terminals was significantly reduced in MGL-knockout mice. These observations highlight the spinal nociceptor synapse as a potential anatomical site for the analgesic effects of MGL blockade. Moreover, the presence of MGL in additional terminal types raises the possibility that MGL may play distinct regulatory roles in synaptic endocannabinoid or prostaglandin signaling according to its different cellular locations in the dorsal horn pain circuitry.
ESTHER : Horvath_2014_Eur.J.Neurosci_39_419
PubMedSearch : Horvath_2014_Eur.J.Neurosci_39_419
PubMedID: 24494682

Title : Augmented tonic pain-related behavior in knockout mice lacking monoacylglycerol lipase, a major degrading enzyme for the endocannabinoid 2-arachidonoylglycerol - Petrenko_2014_Behav.Brain.Res_271_51
Author(s) : Petrenko AB , Yamazaki M , Sakimura K , Kano M , Baba H
Ref : Behavioural Brain Research , 271 :51 , 2014
Abstract : Monoacylglycerol lipase (MGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG). Selective inhibitors of MGL have antinociceptive effects upon acute administration and, therefore, hold promise as analgesics. To gain insight into the possible consequences of their prolonged administration, genetically modified mice with the knocked-out MGL gene were tested in several models of acute (phasic, tonic) and chronic (inflammatory, neuropathic) pain. MGL knockout mice showed normal acute phasic pain perception (pain thresholds) and no alleviation of pain perception in models of inflammatory and neuropathic pain. However, compared with wild-type controls, they showed significantly augmented nociceptive behavior in models of acute somatic and visceral tonic pain (formalin and acetic acid tests). The observed proalgesic changes in perception of tonic pain in MGL knockouts could have resulted from desensitization of cannabinoid receptors (known to occur after genetic inactivation of MGL). Supporting this notion, chronic pretreatment with the selective CB1 receptor antagonist AM 251 (employed to re-sensitize cannabinoid receptors in MGL knockouts) resulted in normalization of their tonic pain-related behaviors. Similar augmentation of tonic pain-related behaviors was replicated in C57BL/6N mice pretreated chronically with the selective MGL inhibitor JZL 184 (employed to pharmacologically desensitize CB1 receptors). These findings imply that prolonged use of MGL inhibitors, at doses causing close to complete inhibition of MGL enzymatic activity, not only have no beneficial analgesic effects, they may lead to exacerbation of some types of pain (particularly those with a tonic component).
ESTHER : Petrenko_2014_Behav.Brain.Res_271_51
PubMedSearch : Petrenko_2014_Behav.Brain.Res_271_51
PubMedID: 24906199

Title : Diacylglycerol lipase alpha manipulation reveals developmental roles for intercellular endocannabinoid signaling - Keimpema_2013_Sci.Rep_3_2093
Author(s) : Keimpema E , Alpar A , Howell F , Malenczyk K , Hobbs C , Hurd YL , Watanabe M , Sakimura K , Kano M , Doherty P , Harkany T
Ref : Sci Rep , 3 :2093 , 2013
Abstract : Endocannabinoids are small signaling lipids, with 2-arachidonoylglycerol (2-AG) implicated in modulating axonal growth and synaptic plasticity. The concept of short-range extracellular signaling by endocannabinoids is supported by the lack of trans-synaptic 2-AG signaling in mice lacking sn-1-diacylglycerol lipases (DAGLs), synthesizing 2-AG. Nevertheless, how far endocannabinoids can spread extracellularly to evoke physiological responses at CB(1) cannabinoid receptors (CB(1)Rs) remains poorly understood. Here, we first show that cholinergic innervation of CA1 pyramidal cells of the hippocampus is sensitive to the genetic disruption of 2-AG signaling in DAGLalpha null mice. Next, we exploit a hybrid COS-7-cholinergic neuron co-culture system to demonstrate that heterologous DAGLalpha overexpression spherically excludes cholinergic growth cones from 2-AG-rich extracellular environments, and minimizes cell-cell contact in vitro. CB(1)R-mediated exclusion responses lasted 3 days, indicating sustained spherical 2-AG availability. Overall, these data suggest that extracellular 2-AG concentrations can be sufficient to activate CB(1)Rs along discrete spherical boundaries to modulate neuronal responsiveness.
ESTHER : Keimpema_2013_Sci.Rep_3_2093
PubMedSearch : Keimpema_2013_Sci.Rep_3_2093
PubMedID: 23806960

Title : Acute inhibition of diacylglycerol lipase blocks endocannabinoid-mediated retrograde signalling: evidence for on-demand biosynthesis of 2-arachidonoylglycerol - Hashimotodani_2013_J.Physiol_591_4765
Author(s) : Hashimotodani Y , Ohno-Shosaku T , Tanimura A , Kita Y , Sano Y , Shimizu T , Di Marzo V , Kano M
Ref : The Journal of Physiology , 591 :4765 , 2013
Abstract : Abstract The endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) produced by diacylglycerol lipase alpha (DGLalpha) is one of the best-characterized retrograde messengers at central synapses. It has been thought that 2-AG is produced 'on demand' upon activation of postsynaptic neurons. However, recent studies propose that 2-AG is pre-synthesized by DGLalpha and stored in neurons, and that 2-AG is released from such 'pre-formed pools' without the participation of DGLalpha. To address whether the 2-AG source for retrograde signalling is the on-demand biosynthesis by DGLalpha or the mobilization from pre-formed pools, we examined the effects of acute pharmacological inhibition of DGL by a novel potent DGL inhibitor, OMDM-188, on retrograde eCB signalling triggered by Ca2+ elevation, Gq/11 protein-coupled receptor activation or synergy of these two stimuli in postsynaptic neurons. We found that pretreatment for 1 h with OMDM-188 effectively blocked depolarization-induced suppression of inhibition (DSI), a purely Ca2+-dependent form of eCB signalling, in slices from the hippocampus, striatum and cerebellum. We also found that at parallel fibre-Purkinje cell synapses in the cerebellum OMDM-188 abolished synaptically induced retrograde eCB signalling, which is known to be caused by the synergy of postsynaptic Ca2+ elevation and group I metabotropic glutamate receptor (I-mGluR) activation. Moreover, brief OMDM-188 treatments for several minutes were sufficient to suppress both DSI and the I-mGluR-induced retrograde eCB signalling in cultured hippocampal neurons. These results are consistent with the hypothesis that 2-AG for synaptic retrograde signalling is supplied as a result of on-demand biosynthesis by DGLalpha rather than mobilization from presumptive pre-formed pools.
ESTHER : Hashimotodani_2013_J.Physiol_591_4765
PubMedSearch : Hashimotodani_2013_J.Physiol_591_4765
PubMedID: 23858009
Gene_locus related to this paper: human-DAGLA

Title : Organotypic coculture preparation for the study of developmental synapse elimination in mammalian brain - Uesaka_2012_J.Neurosci_32_11657
Author(s) : Uesaka N , Mikuni T , Hashimoto K , Hirai H , Sakimura K , Kano M
Ref : Journal of Neuroscience , 32 :11657 , 2012
Abstract : We developed an organotypic coculture preparation allowing fast and efficient identification of molecules that regulate developmental synapse elimination in the mammalian brain. This coculture consists of a cerebellar slice obtained from rat or mouse at postnatal day 9 (P9) or P10 and a medullary explant containing the inferior olive dissected from rat at embryonic day 15. We verified that climbing fibers (CFs), the axons of inferior olivary neurons, formed functional synapses onto Purkinje cells (PCs) in the cerebellum of cocultures. PCs were initially reinnervated by multiple CFs with similar strengths. Surplus CFs were eliminated subsequently, and the remaining CFs became stronger. These changes are similar to those occurring in developing cerebellum in vivo. Importantly, the changes in CF innervations in cocultures involved the same molecules required for CF synapse elimination in vivo, including NMDA receptor, type 1 metabotropic glutamate receptor and glutamate receptor delta2 (GluRdelta2). We demonstrate that gain- and loss-of-function analyses can be efficiently performed by lentiviral-mediated overexpression and RNAi-induced knockdown of GluRdelta2. Using this approach, we identified neuroligin-2 as a novel molecule that promotes CF synapse elimination in postsynaptic PCs. Thus, our coculture preparation will greatly facilitate the elucidation of molecular mechanisms of synapse elimination.
ESTHER : Uesaka_2012_J.Neurosci_32_11657
PubMedSearch : Uesaka_2012_J.Neurosci_32_11657
PubMedID: 22915109

Title : Complementary synaptic distribution of enzymes responsible for synthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in the human hippocampus - Ludanyi_2011_Neurosci_174_50
Author(s) : Ludanyi A , Hu SS , Yamazaki M , Tanimura A , Piomelli D , Watanabe M , Kano M , Sakimura K , Magloczky Z , Mackie K , Freund TF , Katona I
Ref : Neuroscience , 174 :50 , 2011
Abstract : Clinical and experimental evidence demonstrates that endocannabinoids play either beneficial or adverse roles in many neurological and psychiatric disorders. Their medical significance may be best explained by the emerging concept that endocannabinoids are essential modulators of synaptic transmission throughout the central nervous system. However, the precise molecular architecture of the endocannabinoid signaling machinery in the human brain remains elusive. To address this issue, we investigated the synaptic distribution of metabolic enzymes for the most abundant endocannabinoid molecule, 2-arachidonoylglycerol (2-AG), in the postmortem human hippocampus. Immunostaining for diacylglycerol lipase-alpha (DGL-alpha), the main synthesizing enzyme of 2-AG, resulted in a laminar pattern corresponding to the termination zones of glutamatergic pathways. The highest density of DGL-alpha-immunostaining was observed in strata radiatum and oriens of the cornu ammonis and in the inner third of stratum moleculare of the dentate gyrus. At higher magnification, DGL-alpha-immunopositive puncta were distributed throughout the neuropil outlining the immunonegative main dendrites of pyramidal and granule cells. Electron microscopic analysis revealed that this pattern was due to the accumulation of DGL-alpha in dendritic spine heads. Similar DGL-alpha-immunostaining pattern was also found in hippocampi of wild-type, but not of DGL-alpha knockout mice. Using two independent antibodies developed against monoacylglycerol lipase (MGL), the predominant enzyme inactivating 2-AG, immunostaining also revealed a laminar and punctate staining pattern. However, as observed previously in rodent hippocampus, MGL was enriched in axon terminals instead of postsynaptic structures at the ultrastructural level. Taken together, these findings demonstrate the post- and presynaptic segregation of primary enzymes responsible for synthesis and elimination of 2-AG, respectively, in the human hippocampus. Thus, molecular architecture of the endocannabinoid signaling machinery supports retrograde regulation of synaptic activity, and its similar blueprint in rodents and humans further indicates that 2-AG's physiological role as a negative feed-back signal is an evolutionarily conserved feature of excitatory synapses.
ESTHER : Ludanyi_2011_Neurosci_174_50
PubMedSearch : Ludanyi_2011_Neurosci_174_50
PubMedID: 21035522

Title : The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission - Tanimura_2010_Neuron_65_320
Author(s) : Tanimura A , Yamazaki M , Hashimotodani Y , Uchigashima M , Kawata S , Abe M , Kita Y , Hashimoto K , Shimizu T , Watanabe M , Sakimura K , Kano M
Ref : Neuron , 65 :320 , 2010
Abstract : Endocannabinoids are released from postsynaptic neurons and cause retrograde suppression of synaptic transmission. Anandamide and 2-arachidonoylglycerol (2-AG) are regarded as two major endocannabinoids. To determine to what extent 2-AG contributes to retrograde signaling, we generated and analyzed mutant mice lacking either of the two 2-AG synthesizing enzymes diacylglycerol lipase alpha (DGLalpha) and beta (DGLbeta). We found that endocannabinoid-mediated retrograde synaptic suppression was totally absent in the cerebellum, hippocampus, and striatum of DGLalpha knockout mice, whereas the retrograde suppression was intact in DGLbeta knockout brains. The basal 2-AG content was markedly reduced and stimulus-induced elevation of 2-AG was absent in DGLalpha knockout brains, whereas the 2-AG content was normal in DGLbeta knockout brains. Morphology of the brain and expression of molecules required for 2-AG production other than DGLs were normal in the two knockout mice. We conclude that 2-AG produced by DGLalpha, but not by DGLbeta, mediates retrograde suppression at central synapses.
ESTHER : Tanimura_2010_Neuron_65_320
PubMedSearch : Tanimura_2010_Neuron_65_320
PubMedID: 20159446
Gene_locus related to this paper: human-DAGLA

Title : Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release - Hashimotodani_2008_Neuropharmacol_54_58
Author(s) : Hashimotodani Y , Ohno-Shosaku T , Maejima T , Fukami K , Kano M
Ref : Neuropharmacology , 54 :58 , 2008
Abstract : Depolarization-induced suppression of inhibition (DSI) or excitation (DSE) is a well-known form of endocannabinoid-mediated short-term plasticity that is induced by postsynaptic depolarization. It is generally accepted that DSI/DSE is triggered by Ca(2+) influx through voltage-gated Ca(2+) channels. It is also demonstrated that DSI/DSE is mediated by 2-arachidonoylglycerol (2-AG). However, how Ca(2+) induces 2-AG production is still unclear. In the present study, we investigated molecular mechanisms underlying the Ca(2+)-driven 2-AG production. Using cannabinoid-sensitive inhibitory synapses of cultured hippocampal neurons, we tested several inhibitors for enzymes that are supposed to be involved in 2-AG metabolism. The chemicals we tested include inhibitors for phospholipase C (U73122 and ET-18), diacylglycerol kinase (DGK inhibitor 1), phosphatidic acid phosphohydrolase (propranolol), and diacylglycerol lipase (DGL; RHC-80267 and tetrahydrolipstatin (THL)). However, unfavorable side effects were observed with these inhibitors, except for THL. Furthermore, we found that RHC-80267 hardly inhibited the endocannabinoid release driven by G(q/11)-coupled receptors, which is thought to be DGL-dependent. By contrast, THL exhibited no side effects as long as we tested, and was confirmed to inhibit the DGL-dependent process. Using THL as a DGL inhibitor, we demonstrated that DGL is involved in both hippocampal DSI and cerebellar DSE. To test a possible involvement of PLCdelta in DSI, we examined hippocampal DSI in PLCdelta1, delta3 and delta4-knockout mice. However, there was no significant difference in the DSI magnitude between these knockout mice and wild-type mice. The present study clearly shows that DGL is a prerequisite for DSI/DSE. The enzymes yielding DG remain to be determined.
ESTHER : Hashimotodani_2008_Neuropharmacol_54_58
PubMedSearch : Hashimotodani_2008_Neuropharmacol_54_58
PubMedID: 17655882

Title : Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus - Hashimotodani_2007_J.Neurosci_27_1211
Author(s) : Hashimotodani Y , Ohno-Shosaku T , Kano M
Ref : Journal of Neuroscience , 27 :1211 , 2007
Abstract : Endocannabinoids function as retrograde messengers and modulate synaptic transmission through presynaptic cannabinoid CB1 receptors. The magnitude and time course of endocannabinoid signaling are thought to depend on the balance between the production and degradation of endocannabinoids. The major endocannabinoid 2-arachidonoylglycerol (2-AG) is hydrolyzed by monoacylglycerol lipase (MGL), which is shown to be localized at axon terminals. In the present study, we investigated how MGL regulates endocannabinoid signaling and influences synaptic transmission in the hippocampus. We found that MGL inhibitors, methyl arachidonoyl fluorophosphonate and arachidonoyl trifluoromethylketone, caused a gradual suppression of cannabinoid-sensitive IPSCs in cultured hippocampal neurons. This suppression was reversed by blocking CB1 receptors and was attenuated by inhibiting 2-AG synthesis, indicating that MGL scavenges constitutively released 2-AG. We also found that the MGL inhibitors significantly prolonged the suppression of both IPSCs and EPSCs induced by exogenous 2-AG and depolarization-induced suppression of inhibition/excitation, a phenomenon known to be mediated by retrograde endocannabinoid signaling. In contrast, inhibitors of other endocannabinoid hydrolyzing enzymes, fatty acid amide hydrolase and cyclooxygenase-2, had no effect on the 2-AG-induced IPSC suppression. These results strongly suggest that presynaptic MGL not only hydrolyzes 2-AG released from activated postsynaptic neurons but also contributes to degradation of constitutively produced 2-AG and prevention of its accumulation around presynaptic terminals. Thus, the MGL activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus.
ESTHER : Hashimotodani_2007_J.Neurosci_27_1211
PubMedSearch : Hashimotodani_2007_J.Neurosci_27_1211
PubMedID: 17267577

Title : Endocannabinoid signalling triggered by NMDA receptor-mediated calcium entry into rat hippocampal neurons - Ohno-Shosaku_2007_J.Physiol_584_407
Author(s) : Ohno-Shosaku T , Hashimotodani Y , Ano M , Takeda S , Tsubokawa H , Kano M
Ref : Journal de Physiologie , 584 :407 , 2007
Abstract : Endocannabinoids are released from neurons in activity-dependent manners, act retrogradely on presynaptic CB(1) cannabinoid receptors, and induce short-term or long-term suppression of transmitter release. The endocannabinoid release is triggered by postsynaptic activation of voltage-gated Ca(2+) channels and/or G(q)-coupled receptors such as group I metabotropic glutamate receptors (I-mGluRs) and M(1)/M(3) muscarinic receptors. However, the roles of NMDA receptors, which provide another pathway for Ca(2+) entry into neurons, in endocannabinoid signalling have been poorly understood. In the present study, we investigated the possible contribution of NMDA receptors in endocannabinoid production by recording IPSCs in cultured hippocampal neurons. Under the conditions minimizing the activation of voltage-gated Ca(2+) channels, local application of NMDA (200 microm) transiently suppressed cannabinoid-sensitive IPSCs, but not cannabinoid-insensitive IPSCs. This NMDA-induced suppression was abolished by blocking NMDA receptors, CB(1) receptors and diacylglycerol lipase, but not by inhibiting voltage-gated Ca(2+) channels. When the postsynaptic neuron was dialysed with 30 mm BAPTA, the NMDA-induced suppression was reduced significantly. A lower dose of NMDA (20 microm) exerted little effect when applied alone, but markedly enhanced the cannabinoid-dependent suppression driven by muscarinic receptors or I-mGluRs. These data clearly indicate that the activation of NMDA receptors facilitates the endocannabinoid release either alone or in concert with the G(q)-coupled receptors.
ESTHER : Ohno-Shosaku_2007_J.Physiol_584_407
PubMedSearch : Ohno-Shosaku_2007_J.Physiol_584_407
PubMedID: 17615096

Title : Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor - Yoshida_2006_J.Neurosci_26_4740
Author(s) : Yoshida T , Fukaya M , Uchigashima M , Miura E , Kamiya H , Kano M , Watanabe M
Ref : Journal of Neuroscience , 26 :4740 , 2006
Abstract : 2-arachidonoyl-glycerol (2-AG) is an endocannabinoid that is released from postsynaptic neurons, acts retrogradely on presynaptic cannabinoid receptor CB1, and induces short- and long-term suppression of transmitter release. To understand the mechanisms of the 2-AG-mediated retrograde modulation, we investigated subcellular localization of a major 2-AG biosynthetic enzyme, diacylglycerol lipase-alpha (DAGLalpha), by using immunofluorescence and immunoelectron microscopy in the mouse brain. In the cerebellum, DAGLalpha was predominantly expressed in Purkinje cells. DAGLalpha was detected on the dendritic surface and occasionally on the somatic surface, with a distal-to-proximal gradient from spiny branchlets toward somata. DAGLalpha was highly concentrated at the base of spine neck and also accumulated with much lower density on somatodendritic membrane around the spine neck. However, DAGLalpha was excluded from the main body of spine neck and head. In hippocampal pyramidal cells, DAGLalpha was also accumulated in spines. In contrast to the distribution in Purkinje cells, DAGLalpha was distributed in the spine head, neck, or both, whereas somatodendritic membrane was labeled very weakly. These results indicate that DAGLalpha is essentially targeted to postsynaptic spines in cerebellar and hippocampal neurons, but its fine distribution within and around spines is differently regulated between the two neurons. The preferential spine targeting should enable efficient 2-AG production on excitatory synaptic activity and its swift retrograde modulation onto nearby presynaptic terminals expressing CB1. Furthermore, different fine localization within and around spines suggests that the distance between postsynaptic 2-AG production site and presynaptic CB1 is differentially controlled depending on neuron types.
ESTHER : Yoshida_2006_J.Neurosci_26_4740
PubMedSearch : Yoshida_2006_J.Neurosci_26_4740
PubMedID: 16672646