Theoretical and modeling studies demonstrate that heterosynaptic plasticity—changes at synapses inactive during induction—facilitates fine-grained discriminative learning in Hebbian-type systems, and helps to achieve a robust ability for repetitive learning. A dearth of tools for selective manipulation has hindered experimental analysis of the proposed role of heterosynaptic plasticity in behavior. Here we circumvent this obstacle by testing specific predictions about the behavioral consequences of the impairment of heterosynaptic plasticity by experimental manipulations to adenosine A1 receptors (A1Rs). Our prior work demonstrated that the blockade of adenosine A1 receptors impairs heterosynaptic plasticity in brain slices and, when implemented in computer models, selectively impairs repetitive learning on sequential tasks. Based on this work, we predict that A1R knock-out (KO) mice will express (1) impairment of heterosynaptic plasticity and (2) behavioral deficits in learning on sequential tasks. Using ...