Altered heterosynaptic plasticity impairs visual discrimination learning in adenosine A1 receptor knockout mice

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 changes in heterosynaptic plasticity, and associated behavioral consequences, following experimental manipulation of adenosine A1 receptors (A1R). We show that, compared to wild-type controls, A1R-knockout mice have impaired synaptic plasticity in visual cortex neurons, coupled with significant deficits in visual discrimination learning. Deficits in A1R-knockouts were seen specifically during re-learning, becoming progressively more apparent with learning on sequential visual discrimination tasks of increasing complexity. These behavioral results confirm our model predictions, and provide the first experimental evidence for a proposed role of heterosynaptic plasticity in learning. HighlightsO_LISynaptic plasticity is impaired in visual cortex neurons in adenosine A1R knockout mice C_LIO_LIHomosynaptic and heterosynaptic plasticity in A1R KO mice is dominated by depression C_LIO_LILearning on sequential, increasingly complex visual tasks is impaired in A1R KO mice C_LIO_LILearning deficits match predicted effects of impaired heterosynaptic plasticity C_LI