Spike encoding at GABAergic neurons plays an important role in maintaining the homeostasis of brain functions for well-organized behaviors. The rise of intracellular Ca2+ in GABAergic neurons causes synaptic plasticity. It is not clear how intracellular Ca2+ influences their spike encoding. We have investigated this issue at GFP-labeled GABAergic cortical neurons and cerebellar Purkinje cells by whole-cell recording in mouse brain slices. Our results show that an elevation of intracellular Ca2+ by infusing adenophostin-A lowers spike encoding at GABAergic cortical neurons and enhances encoding ability at cerebellar Purkinje cells. These differential effects of cytoplasmic Ca2+ on spike encoding are mechanistically associated with Ca2+-induced changes in the refractory periods and threshold potentials of sequential spikes, as well as with various expression ratios of CaM-KII to calcineurin in GABAergic cortical neurons and cerebellar Purkinje cells.