Small-conductance calcium-activated potassium channels (K Ca 2) are essential components involved in the modulation of neuronal excitability, underlying learning and memory. Recent evidence suggests that K Ca 2 channel activity reduces synaptic transmission in a postsynaptic NMDA receptor-dependent manner and is modulated by long-term potentiation. We used radioactive in situ hybridization and apamin binding to investigate the amount of K Ca 2 subunit mRNA and K Ca 2 proteins in brain structures involved in learning and memory at different stages of a radial-arm maze task in naive, pseudoconditioned, and conditioned rats. We observed significant differences in K Ca 2.2 and K Ca 2.3, but not K Ca 2.1 mRNA levels, between conditioned and pseudoconditioned rats. K Ca 2.2 levels were transiently reduced in the dorsal CA fields of the hippocampus, whereas K Ca 2.3 mRNA levels were reduced in the dorsal and ventral CA fields of the hippocampus, entorhinal cortex, and basolateral amygdaloid nucleus in conditioned rats, during early stages of learning. Levels of apamin-binding sites displayed a similar pattern to K Ca 2 mRNA levels during learning. Spatial learning performance was positively correlated with levels of apamin-binding sites and K Ca 2.3 mRNA in the dorsal CA1 field and negatively correlated in the dorsal CA3 field. These findings suggest that K Ca 2 channels are transiently downregulated in the early stages of learning and that regulation of K Ca 2 channel levels is involved in the modification of neuronal substrates underlying new information acquisition. V V