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To test if VOCCs are centrally involved in triggering astrocyte reactivity, we used <jats:italic>in vitro<\/jats:italic> models of astrocyte activation in combination with pharmacological inhibitors, siRNAs and the Cre\/lox system to reduce the activity of L\u2010type VOCCs in primary cortical astrocytes. The endotoxin lipopolysaccharide (LPS) as well as high extracellular K<jats:sup>+<\/jats:sup>, glutamate, and ATP promote astrogliosis <jats:italic>in vitro<\/jats:italic>. L\u2010type VOCC inhibitors drastically reduce the number of reactive cells, astrocyte hypertrophy, and cell proliferation after these treatments. Astrocytes transfected with siRNAs for the Cav1.2 subunit that conducts L\u2010type Ca<jats:sup>++<\/jats:sup> currents as well as Cav1.2 knockout astrocytes showed reduce Ca<jats:sup>++<\/jats:sup> influx by \u223c80% after plasma membrane depolarization. Importantly, Cav1.2 knock\u2010down\/out prevents astrocyte activation and proliferation induced by LPS. Similar results were found using the scratch wound assay. After injuring the astrocyte monolayer, cells extend processes toward the cell\u2010free scratch region and subsequently migrate and populate the scratch. We found a significant increase in the activity of L\u2010type VOCCs in reactive astrocytes located in the growing line in comparison to quiescent astrocytes situated away from the scratch. Moreover, the migration of astrocytes from the scratching line as well as the number of proliferating astrocytes was reduced in Cav1.2 knock\u2010down\/out cultures. In summary, our results suggest that Cav1.2 L\u2010type VOCCs play a fundamental role in the induction and\/or proliferation of reactive astrocytes, and indicate that the inhibition of these Ca<jats:sup>++<\/jats:sup> channels may be an effective way to prevent astrocyte activation. GLIA 2016. 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