Methamphetamine exposure drives cell cycle exit and aberrant differentiation in rat hippocampal-derived neurospheres

Abstract

Introduction: Methamphetamine (METH) abuse by pregnant drug addicts causes toxic effects on fetal neurodevelopment; however, the mechanism underlying such effect of METH is poorly understood.Methods: In the present study, we applied three-dimensional (3D) neurospheres derived from the embryonic rat hippocampal tissue to investigate the effect of METH on neurodevelopment. Through the combination of whole genome transcriptional analyses, the involved cell signalings were identified and investigated.Results: We found that METH treatment for 24 h significantly and concentration-dependently reduced the size of neurospheres. Analyses of genome-wide transcriptomic profiles found that those down-regulated differentially expressed genes (DEGs) upon METH exposure were remarkably enriched in the cell cycle progression. By measuring the cell cycle and the expression of cell cycle-related checkpoint proteins, we found that METH exposure significantly elevated the percentage of G0/G1 phase and decreased the levels of the proteins involved in the G1/S transition, indicating G0/G1 cell cycle arrest. Furthermore, during the early neurodevelopment stage of neurospheres, METH caused aberrant cell differentiation both in the neurons and astrocytes, and attenuated migration ability of neurospheres accompanied by increased oxidative stress and apoptosis.Conclusion: Our findings reveal that METH induces an aberrant cell cycle arrest and neuronal differentiation, impairing the coordination of migration and differentiation of neurospheres.

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“…Additionally, METH induced novel networks of astrocytespecific gene expression that control cytokine responses and the inflammasome, resulting in modifications to the RNA and protein levels of neuroinflammatory and cytokine gene expression [66]. After being exposed to METH, neutrospheres made from embryonic rat hippocampal tissue displayed abnormal cell differentiation in both neurons and astrocytes, as well as a decreased capacity for neutrosphere migration coupled with an increase in oxidative stress and apoptosis [67]. Taken together, the scRNA-seq literature overview demonstrated that COC mainly influences neurons in VTA and NAc, while METH has a primary influence on the immune response.…”