Learning is widely believed to involve synaptic plasticity, using mechanisms such as those used in long-term potentiation (LTP). We assess whether the mechanisms used in alternative forms of plasticity, long-term depression (LTD) and depotentiation, play a role in learning. We have exploited the involvement of the perirhinal cortex in two different forms of learning to compare simultaneously, within the same brain region, their effects on LTD and depotentiation. Multiple-exposure learning but not single-exposure learning in vivo prevented, in a muscarinic receptor-dependent manner, subsequent induction of LTD and depotentiation, but not LTP, in perirhinal cortex in vitro. The contrast in the effects of the two types of learning under these particular experimental conditions indicate that the in vitro change is unlikely to be attributable to synapse-specific plastic changes registering the precise details of the individual learned associations. Instead, it is concluded that the lack of LTD and depotentiation arises from, and establishes the importance of, a learning-related generalized change in plasticity gain. The existence of this additional mechanism has important implications for interpretations of how plasticity relates to learning.