Abstract
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.
Highlights
THC binds to CB1Rs and induces neuronal activity in juvenile mice
In utero exposure to THC or synthetic CB1R agonists [56] selectively reduces the number, morphological complexity, and local innervation of CCK+/CB1R+ interneurons [12, 57] in the fetal hippocampus and leaves adaptive neuronal plasticity permanently reduced in affected offspring [11]
We tested if incrementing concentrations of plant-derived THC displace [3H]CP55,940 (0.5 nM): the half-maximal inhibitory concentration for pTHC (IC50) remained unchanged throughout (37 ± 9 nM [E18.5], 25 ± 4 nM [P2], 28 ± 8 nM [P16], and 25 ± 2 nM [adult]; P > 0.3; Supplemental Figure 1C)
Summary
The ongoing legalization of cannabis products triggered a sea change in preference to preparations with high psychoactive potency, with some oils and waxes reaching more than 90% of Δ9-tetrahydrocannabinol (THC) content [1, 2] These trends, together with the increased accessibility of THC-containing products to even young age groups, suggest that, besides adverse metabolic symptoms in adults The stabilization and selection of synaptic contacts that drive meaningful information in corticolimbic networks together with postnatal avalanches of programmed cell death that reduce neuronal redundancy [23, 24] can be sensitive to exposure to psychoactive drugs, such as THC [25] These notions are congruent with neuroanatomical changes Our data define key sites and mechanisms of neuronal vulnerability to THC and offer prototypic strategies of rescue, at least in vitro
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