Synthetic Cannabinoids: Unexpected Impacts on Brain Cell Development

Mitochondria are essential drivers of neuronal growth, differentiation, and overall brain development. Synthetic cannabinoids (SCs) have been shown to enhance neurite outgrowth in NG108-15 neuroblastoma x glioma cells through CB1 receptor activation, while disrupting mitochondrial function. Here, we demonstrated first-hand the impact of biologically-relevant concentrations (< 1μM) of ADB-FUBINACA (an SC commonly identified in drug seizures) on mitochondrial morphology and dynamics (i.e., fusion, fission and mobility) during the neurodifferentiation of NG108-15 cells. Our findings revealed that, during NG108-15 neurodifferentiation, ADB-FUBINACA reduced the mean mitochondrial area and perimeter by around 10%, while increasing mitochondrial circularity, and decreasing network branching and interconnectivity. Specifically, branch length per mitochondrion and branch junctions declined by 17 and 25% in the neurons' soma at the end of NG108-15 differentiation (after 72 h). Moreover, 1 nM and 1 µM ADB-FUBINACA markedly decreased the levels of mitochondrial fusion markers (Opa1 and Mfn2) and increased the levels of fission markers Drp1 and Fis1 at the same time point. The percentage of motile mitochondria in neurites also decreased at 72 h, while average speed and total run length per mobile mitochondrion remained unaffected, resulting in an accumulation of stationary mitochondria which may be important, for example, to support neurite extension. Collectively, these findings suggest that while ADB-FUBINACA promotes mitochondrial accumulation in neurites, potentially supporting the energy demands of developing neurites and influencing neurite outgrowth, in the long-term, the fragmentation of the mitochondrial network in the soma may compromise the maintenance of neurites, in terms of energy requirements.