TY - JOUR AU - Tortoriello, G AU - Morris, CV AU - Alpár, Alán AU - Fuzik, J AU - Shirran, SL AU - Calvigioni, D AU - Keimpema, E AU - Botting, CH AU - Reinecke, K AU - Herdegen, T AU - Courtney, M AU - Hurd, YL AU - Harkany, T TI - Miswiring the brain: Δ9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway JF - EMBO JOURNAL J2 - EMBO J VL - 33 PY - 2014 IS - 7 SP - 668 EP - 685 PG - 18 SN - 0261-4189 DO - 10.1002/embj.201386035 UR - https://m2.mtmt.hu/api/publication/2718517 ID - 2718517 AB - Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Δ9-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor-driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC-sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin-2, a microtubule-binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis-exposed fetuses, defining SCG10 as the first cannabis-driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c-Jun N-terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring. © 2014 The Authors. LA - English DB - MTMT ER - TY - JOUR AU - Palkovits, Miklós AU - Harvey-White, J AU - Liu, J AU - Kovács, Zsolt AU - Bobest, M AU - Lovas, Gábor AU - Bagó, Attila György AU - Kunos, G TI - Regional distribution and effects of postmortal delay on endocannabinoid content of the human brain JF - NEUROSCIENCE J2 - NEUROSCIENCE VL - 152 PY - 2008 IS - 4 SP - 1032 EP - 1039 PG - 8 SN - 0306-4522 DO - 10.1016/j.neuroscience.2008.01.034 UR - https://m2.mtmt.hu/api/publication/1120873 ID - 1120873 N1 - Neuromorphological and Neuroendocrine Research Laboratory, the Semmelweis University, the Hungarian Academy of Sciences, 1094 Budapest, Hungary Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, United States Department of Zoology, University of West Hungary, 9700 Szombathely, Hungary Markusovszky Hospital, 9700 Szombathely, Hungary Department of Neurology, Semmelweis University, 1083 Budapest, Hungary National Institute of Neurosurgery, 1145 Budapest, Hungary Cited By :43 Export Date: 13 July 2023 CODEN: NRSCD Correspondence Address: Palkovits, M.; Neuromorphological and Neuroendocrine Research Laboratory, , 1094 Budapest, Hungary; email: palkovits@ana.sote.hu Chemicals/CAS: anandamide, 94421-68-8; 2-arachidonylglycerol, 53847-30-6; anandamide, 94421-68-8; Arachidonic Acids; Glycerides; Polyunsaturated Alkamides Funding details: National Institutes of Health, NIH Funding details: National Institute on Alcohol Abuse and Alcoholism, NIAAA, Z01AA000350 Funding details: European Commission, EC, LSHM-CT-2004-503036 Funding text 1: This research was supported by EU Grant FP6, BNEII No. LSHM-CT-2004-503036 to the Human Brain Tissue Bank, Budapest (to M.P.) and funds from the Intramural Program of the NIH (to G.K.). AB - Tissue levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have been determined in 16 regions and nuclei from human brains, using liquid chromatography/in-line mass spectrometry. Measurements in brain samples stored at −80 °C for 2 months to 13 years indicated that endocannabinoids were stable under such conditions. In contrast, the postmortal delay had a strong effect on brain endocannabinoid levels, as documented in brain samples microdissected and frozen 1–6 h postmortem, and in neurosurgical samples 0, 5, 30, 60, 180 and 360 min after their removal from the brain. The tissue levels of AEA increased continuously and in a region-dependent manner from 1 h after death, increasing about sevenfold by 6 h postmortem. In contrast, concentrations of 2-AG, which were 10–100 times higher in human brain regions than those of AEA, rapidly declined: within the first hour, 2-AG levels dropped to 25–35% of the initial (‘0 min’) value, thereafter they remained relatively stable. As analyzed in samples removed 1–1.5 h postmortem, AEA levels ranged from a high of 96.3 fmol/mg tissue in the nucleus accumbens to a low of 25.0 fmol/mg in the cerebellum. 2-AG levels varied eightfold, from 8.6 pmol/mg in the lateral hypothalamus to 1.1 pmol/mg in the nucleus accumbens. Relative levels of AEA and 2-AG varied from region to region, with the 2-AG:AEA ratio being high in the sensory spinal trigeminal nucleus (140:1), the spinal dorsal horn (136:1) and the lateral hypothalamus (98:1) and low in the nucleus accumbens (16:1) and the striatum (31:1). The results highlight the pitfall of analyzing endocannabinoid content in brain samples of variable postmortal delay, and document differential distribution of the two main endocannabinoids in the human brain. LA - English DB - MTMT ER -