PMID- 21035522 OWN - NLM STAT- MEDLINE DCOM- 20110621 LR - 20220129 IS - 1873-7544 (Electronic) IS - 0306-4522 (Print) IS - 0306-4522 (Linking) VI - 174 DP - 2011 Feb 3 TI - Complementary synaptic distribution of enzymes responsible for synthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in the human hippocampus. PG - 50-63 LID - 10.1016/j.neuroscience.2010.10.062 [doi] AB - 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. CI - Copyright A(c) 2011 IBRO. All rights reserved. FAU - Ludanyi, A AU - Ludanyi A AD - Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083, Szigony utca 43, Hungary. FAU - Hu, S S-J AU - Hu SS FAU - Yamazaki, M AU - Yamazaki M FAU - Tanimura, A AU - Tanimura A FAU - Piomelli, D AU - Piomelli D FAU - Watanabe, M AU - Watanabe M FAU - Kano, M AU - Kano M FAU - Sakimura, K AU - Sakimura K FAU - Magloczky, Z AU - Magloczky Z FAU - Mackie, K AU - Mackie K FAU - Freund, T F AU - Freund TF FAU - Katona, I AU - Katona I LA - eng GR - MH54671/MH/NIMH NIH HHS/United States GR - R01 MH054671/MH/NIMH NIH HHS/United States GR - R01 NS030549/NS/NINDS NIH HHS/United States GR - P01 DA009158/DA/NIDA NIH HHS/United States GR - DA021696/DA/NIDA NIH HHS/United States GR - 243153/ERC_/European Research Council/International GR - DA011322/DA/NIDA NIH HHS/United States GR - R37 NS030549/NS/NINDS NIH HHS/United States GR - R01 DA011322/DA/NIDA NIH HHS/United States GR - NS030549/NS/NINDS NIH HHS/United States GR - K05 DA021696/DA/NIDA NIH HHS/United States GR - DA09158/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20101028 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Arachidonic Acids) RN - 0 (Cannabinoid Receptor Modulators) RN - 0 (Endocannabinoids) RN - 0 (Glycerides) RN - 8D239QDW64 (glyceryl 2-arachidonate) RN - EC 3.1.1.34 (DAGLA protein, human) RN - EC 3.1.1.34 (Lipoprotein Lipase) SB - IM EIN - Neuroscience. 2011 Jul 14;186:220 MH - Animals MH - Arachidonic Acids/*metabolism MH - Cannabinoid Receptor Modulators/*metabolism MH - Dendritic Spines/enzymology MH - *Endocannabinoids MH - Glycerides/*metabolism MH - Hippocampus/*metabolism/ultrastructure MH - Humans MH - Immunohistochemistry MH - Lipoprotein Lipase/genetics/*metabolism MH - Mice MH - Mice, Knockout MH - Organ Specificity MH - Presynaptic Terminals/enzymology MH - Signal Transduction MH - Species Specificity MH - Synapses/*enzymology PMC - PMC3678284 MID - NIHMS468627 EDAT- 2010/11/03 06:00 MHDA- 2011/06/22 06:00 PMCR- 2013/06/11 CRDT- 2010/11/02 06:00 PHST- 2010/08/24 00:00 [received] PHST- 2010/10/08 00:00 [revised] PHST- 2010/10/21 00:00 [accepted] PHST- 2010/11/02 06:00 [entrez] PHST- 2010/11/03 06:00 [pubmed] PHST- 2011/06/22 06:00 [medline] PHST- 2013/06/11 00:00 [pmc-release] AID - S0306-4522(10)01417-X [pii] AID - 10.1016/j.neuroscience.2010.10.062 [doi] PST - ppublish SO - Neuroscience. 2011 Feb 3;174:50-63. doi: 10.1016/j.neuroscience.2010.10.062. Epub 2010 Oct 28.