Adverse effects of Δ9-tetrahydrocannabinol on neuronal bioenergetics during postnatal development.
JCI Insight. 2020 Nov 03;:
Authors: Beiersdorf J, Hevesi Z, Calvigioni D, Pyszkowski J, Romanov RA, Szodorai E, Lubec G, Shirran SL, Botting CH, Kasper S, Guy GW, Gray RA, Di Marzo V, Harkany T, Keimpema E
Ongoing societal changes in views on medical and recreational roles of cannabis increased the use of concentrated plant extracts with a Δ9-tetrahydrocannabinol (THC) content of >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 postnatal days (P)5-16 and P5-35 and monitored its effects on hippocampal neuronal survival and specification by high resolution imaging and the hippocampal proteome by iTRAQ proteomics, respectively. We find 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 a large part, render cellular bioenergetics insufficient to sustain key developmental processes in otherwise healthy neurons.
PMID: 33141759 [PubMed – as supplied by publisher]
Source: ncbi 2