Resident Astrocytes can Limit Injury to Developing Hippocampal Neurons upon THC Exposure.

Long-term postnatal exposure to THC, the main psychoactive compound in cannabis, causes hippocampal astrocytes to accumulate in specific regions of the CA1 subfield that contain neurons especially sensitive to stressors. This altered distribution does not depend on cell proliferation, suggesting resident astrocytes gather to protect pyramidal neurons and their extensions from damage. In vitro experiments confirm that astrocytes physically reduce death of primary hippocampal neurons exposed to THC at concentrations above 5 µM. However, astrocytes themselves are affected by a reduced metabolic readiness to stressors, reflected by downregulation of mitochondrial proteins. Thus, astrocytes exert protective functions on local neurons during THC exposure even though their mitochondrial electron transport chain is disrupted.

Study at a glance

Abstract

Cannabis legalization prompted the dilemma if plant-derived recreational drugs can have therapeutic potential and, consequently, how to address their regulation and safe distribution. In parallel, the steady worldwide decriminalization of cannabis and the enhanced content of its main psychoactive compound Δ9-tetrahydrocannabinol (THC), exposes populations to increasing amounts of cannabis and THC across all ages. While adverse effects of cannabis during critical stages of fetal neurodevelopment are investigated, these studies center on neurons alone. Thus, a gap of knowledge exists on how intercellular interactions between neighboring cell types, particularly astrocytes and neurons, could modify THC action. Here, we combine transcriptome analysis, transgenic models, high resolution microscopy and live cell imaging to demonstrate that hippocampal astrocytes accumulate in the strata radiatum and lacunosum moleculare of the CA1 subfield, containing particularly sensitive neurons to stressors, upon long term postnatal THC exposure in vivo. As this altered distribution is not dependent on cell proliferation, we propose that resident astrocytes accumulate in select areas to protect pyramidal neurons and their neurite extensions from pathological damage. Indeed, we could recapitulate the neuroprotective effect of astrocytes in vitro, as their physical presence significantly reduced the death of primary hippocampal neurons upon THC exposure (> 5 µM). Even so, astrocytes are also affected by a reduced metabolic readiness to stressors, as reflected by a downregulation of mitochondrial proteins. Thus, we find that astrocytes exert protective functions on local neurons during THC exposure, even though their mitochondrial electron transport chain is disrupted.