Adverse effects of Δ9-tetrahydrocannabinol on neuronal bioenergetics during postnatal development
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Ongoing societal changes in views on the medical and recreational roles of cannabis increased the use of concentrated plant extracts with a Δ9-tetrahydrocannabinol (THC) content of more than 90%. Even though prenatal THC exposure is widely considered adverse for neuronal development, equivalent experimental data for young age cohorts are largely lacking. Here, we administered plant-derived THC (1 or 5 mg/kg) to mice daily during P5–P16 and P5–P35 and monitored its effects on hippocampal neuronal survival and specification by high-resolution imaging and iTRAQ proteomics, respectively. We found that THC indiscriminately affects pyramidal cells and both cannabinoid receptor 1+ (CB1R)+ and CB1R– interneurons by P16. THC particularly disrupted the expression of mitochondrial proteins (complexes I–IV), a change that had persisted even 4 months after the end of drug exposure. This was reflected by a THC-induced loss of membrane integrity occluding mitochondrial respiration and could be partially or completely rescued by pH stabilization, antioxidants, bypassed glycolysis, and targeting either mitochondrial soluble adenylyl cyclase or the mitochondrial voltage-dependent anion channel. Overall, THC exposure during infancy induces significant and long-lasting reorganization of neuronal circuits through mechanisms that, in large part, render cellular bioenergetics insufficient to sustain key developmental processes in otherwise healthy neurons.
Beiersdorf , J , Hevesi , Z , Calvigioni , D , Pyszkowski , J , Romanov , R , Szodorai , E , Lubec , G , Shirran , S , Botting , C H , Kasper , S , Guy , G W , Gray , R , Di Marzo , V , Harkany , T & Keimpema , E 2020 , ' Adverse effects of Δ 9 -tetrahydrocannabinol on neuronal bioenergetics during postnatal development ' , JCI Insight , vol. 5 , no. 23 , e135418 . https://doi.org/10.1172/jci.insight.135418
Copyright: © 2020, Beiersdorf et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
DescriptionThis work was supported by a grant from FWF (P 34121-B; EK), GW Pharmaceuticals, as well as funding from the Swedish Research Council (2018-02838; TH), the European Research Council (SECRET-CELLS, ERC-2015-AdG-695136; TH), and the Wellcome Trust (grant no. 094476/Z/10/Z, which funded the purchase of the TripleTOF 5600 mass spectrometer at the BSRC Mass Spectrometry and Proteomics Facility, University of St. Andrews).
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